CAAT - Where the Money Goes 2002

Oregon National Primate Research Center INSTITUTION
2002 TOTAL: $24,251,394
Abstracts

1C06RR013585-01
EXTRAMURAL RESEARACH FACILITIES CONSTRUCTION PROJECTS
#N/A
KOHLER, PETER

Abstract: The proposed construction provides housing for non-human primates (NHPs) in a state-of-the-art facility that complies with applicable policies and standards. Programmatic growth in three areas necessitates additional housing for NHPs. First is the production of clonally-derived animals. Successful production of nuclear embryo transplant primates at ONPRC has been met with an unprecedented demand from the scientific community for access to this resource, since clonally-derived animals eliminate genotypic variation. Special funding was provided to enhance and accelerate development of this program (RR12804, AI42709). The recent addition of Dr. Gerald Schatten to direct the Assisted Reproductive Technology Laboratory at ONPRC will allow the development and utilization of these unique NHPs as the most clinically relevant models for human disease. Second is the relocation of the R.S. Dow Neuroscience Institute to ONPRC (the OHSU West Campus) effective January 1, 2000. This group of approximately 20 scientists and their staff will occupy new laboratory space, presently in the design stage. This Institute will double the number of PIs on our campus pacing additional demands on NHP housing. Third is in infectious disease research. Within three years, the number of PIs in infectious disease research will double, from four to eight. To accommodate the requirement for a substantial increase in ABL 2 and ABL 3 containment space to house animals involved in infectious disease research, the ONPRC will renovate older animal space to meet these needs, reducing the space available for conventional housing. The new facility provides modern facilities housing for approximately 368 NHPs.
Thesaurus Terms: animal colony, biomedical facility, building /facility design /renovation

Institution: OREGON REGIONAL PRIMATE RESEARCH CENTER
BEAVERTON, OR 97006
Fiscal Year: 1998
Department:
Project Start: 15-SEP-1998
Project End: 14-SEP-2002
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: STRB

1C06RR014505-01
SHELTERED ANIMAL HOUSING FOR REGIONAL PRIMATE CENTER
#N/A
KOHLER, PETER

Abstract: The proposed construction provides new innovative sheltered housing for non-human primates (NHPs) and will replace the 30 year old outdoor open corrals that presently house our primate production colony. There are a number of reasons that have led us to construct alternative housing to replace the open corrals. First, programmatic growth necessitates the expansion of the production colony. The research program at the Oregon National Primate Research Center (ONPRC) has nearly doubled (in terms of research dollars and number of NHPs assigned to research projects) since 1994. This rate of growth is expected to continue for several reasons. 1) Special funding to enhance the program to produce clonally- derived NHPs, 2) The expansion in infectious disease research, and 3) The relocation of the R.S. Dow Neurological Sciences Institute to the ONPRC campus. By converting the open free ranging corrals into 20 shelter housing units (each holding from 25-30 NPHs), the number of production animals can be increased from 100-150 to 500-600 in the same amount of space. Second, USDA regulations and standards discourage raising animals in an open outdoor corral setting. The sheltered facilities will assure that animals are housed and bred in an environment that meets high animal care standards. The enclosed sheltered housing units will: 1) permit efficient and thoroughly daily sanitation of the animals' environment, 20 allow safe access to the animals, 3) permit options of social interactions, and 4) will comply with all NIH guidelines, AAALAC recommendations, and other applicable federal and local regulations. Third, the City of Hillsboro's (the local government in which ONPRC resides) MasterPlan mandates that existing corrals be decommissioned and no additional "open" animal housing be developed. Our five year plan coverts one of our 2-acre corrals into the area that contains the 20 sheltered housing facilities. The proposal requests funds to begin the first phase of construction; funds are requested to construct 8 sheltered housing units that will hold 25-30 NHPs each.

Thesaurus Terms: animal colony, biomedical facility, building /facility design /renovation

Fiscal Year: 1999
Department: MEDICINE
Project Start: 30-SEP-1999
Project End: 29-SEP-2002
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: STRB

1C06RR017585-01
EXTRAMURAL RESEARCH FACILITIES CONSTRUCTION
$2,000,000
KOHLER, PETER

Abstract: DESCRIPTION (provided by applicant): This application requests funds to construct Phase II infill to the Animal Services Building (ASB) addition that will provide housing for 544 non-human primates (NHPs) in an 11,970 sq. ft. state-of-the art facility. The expansion will enable the Oregon National Primate Research Center (ONPRC) to meet rapidly growing research needs, as well as comply with new United States Department of Agriculture (USDA) mandated standards for expanded social housing. The Oregon Health and Science University (OHSU) made a major commitment by providing approximately $4 million in funds to construct a 35,600 sq. ft. shell addition to the ASB. Phase I infill consists of a 13,000 sq. ft. facility that will house up to 192 NHPs, as well as provide behavioral testing rooms, and office and new cage wash areas. Rapid growth in various research areas necessitates additional NHP housing. Current NHP housing is full, resulting in the following problems: 1) limited ability to meet the needs of existing research programs or begin new projects; 2) delayed procurement of needed animals; 3) delayed renovations due to lack of flex space; and 4) delayed implementation of social housing. The Specific Aims of this application are to construct Phase II infill of the ASB addition, consisting of Animal Biosafety Level 2 (ABL2) containment housing for up to 544 NHPs in 17 animal holding rooms, a feed storage room and a procedure room. Each animal holding room will contain 32 NHPs in paired cages, as well as large group play enclosures to permit groups of animals to regularly experience an enhanced social environment.

Thesaurus Terms: There are no thesaurus terms on file for this project.

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 15-SEP-2002
Project End: 14-SEP-2004
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: STRB

1R01HD042000-01
Epoxyeicosatrienoic Acids in the Ovulatory Follicle
$310,952
Hennebold, Jon D

Abstract: This abstract is not available.

Thesaurus Terms:There are no thesaurus terms on file for this project.

Department: NONE
Project Start: 01-JUN-2002
Project End: 31-MAY-2007
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: REN

1R13RR017070-01
WORKSHOP/USE OF NONHUMAN PRIMATES/NEUROSCIENCE RESEARCH
$31,658
Ojeda, Sergio R

Abstract: The deleterious effects of maternal smoking during pregnancy are all too well established. Maternal smoking is the major preventable cause of intrauterine growth retardation and prematurity. Perhaps less well appreciated, is the recent, overwhelming evidence, that smoking during pregnancy directly and adversely effects lung development. Respiratory problems associated with in utero tobacco exposure include decreased lung function, increased respiratory diseases and increased incidence of sudden infant death syndrome (SIDS). Given the unfortunate prevalence of smoking during pregnancy and the resulting serious consequences, it is of major importance to understand the mechanisms underlying smoking-induced changes in the newborn. Our preliminary data suggests that nicotine itself is one of the factors responsible for the changes in pulmonary function observed in neonates born to smoking mothers. In this application we propose to use the rhesus monkey to characterize the effects of chronic exposure to low levels of nicotine throughout pregnancy on lung development and subsequent pulmonary function. Whole animal studies will be complemented with in vitro studies to begin to determine the molecular mechanisms underlying nicotine's effect on lung. In preliminary studies we have demonstrated that exposure of pregnant rhesus monkeys to a nicotine dose consistent with that of smokers alters fetal airway development and that related effects can be produced in fetal monkey lung organ cultured. Immunohistochemistry shows wide expression of nicotinic receptors in developing lung and nicotine appears to alter the pattern of receptor expression. Preliminary data further suggests that some of the effects of nicotine, acting through nicotinic receptors, may be mediated by antagonism of the mitogenic effects of peptide growth factors. Thus we specifically propose to 1, Determine the basis for nicotine's actions by determining the time course and cell specific expression of nicotinic receptor subtype expression in fetal monkey lung; 2, Characterize the effect of fetal exposure to nicotine on lung development and function by functional, morphometric, immunohistochemical and molecular analysis; and 3, begin to determine the mechanism underlying nicotine's actions by use of fetal monkey lung organ culture. From these studies will come the first description of the effects of chronic nicotine exposure on lung function; a determination of the extent to which these effects are reversible; and a beginning understanding of the mechanisms underlying these effects. Definitive knowledge of the effects of nicotine on lung development would provide an important additional tool in smoking control and will begin to better explain the link between maternal smoking and altered neonatal respiratory function.

Thesaurus Terms:
embryo /fetus toxicology, histogenesis, lung, nicotine, respiratory function
biological model, gastrin releasing peptide, nicotinic receptor, receptor expression
Macaca mulatta, immunocytochemistry, in situ hybridization, organ culture, polymerase chain reaction

Fiscal Year: 2002
Department: NONE
Project Start: 01-FEB-1999
Project End: 31-JAN-2004
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: LBPA

1R21NS041601-01A1
Characterization and Differentiation of Monkey ES Cells
$151,050
Pau, K-Y F

Abstract: DESCRIPTION (provided by applicant): The application of embryonic stem (ES) cell therapy for the treatment of human degenerative diseases should be performed in nonhuman primates prior to human trials. The macaque is an ideal animal model for neural transplantation studies because the developmental potential of the grafted cells can be timely and precisely examined postmortem. As a prelude to in vivo studies, the developmental potential and cell lineage differentiation of monkey ES cells must be established in vitro. To this end, we propose to culture and characterize monkey ES cells free of feeder cells before differentiating them into high-percentage cholinergic and dopaminergic neurons, and to determine the pluripotency of monkey ES cells by single cell culture and spontaneously differentiation into cells of all three embryonic germ layers in vitro, thereby addressing the objectives of this PA (PA-99-086/-01-076, NOVEL APPROACHES TO ENHANCE STEM CELL RESEARCH). Aim 1 will characterize two monkey ES cell lines with an XX and XY karyotype that are cultured under feeder cell-free conditions. Rhesus monkey ES cells will be plated on Matrigel- or laminin-coated dishes and cultured in a serum-free medium supplemented with fibroblast growth factors (FGFs), laminin, serum replacement, or conditioned medium from cell cultures to sustain the pluripotency and undifferentiated states. The growth rate, karyotype normalcy, and undifferentiated state will be determined. Aim 2 will directionally differentiate monkey ES cells into dopaminergic and cholinergic neurons, and to differentiate single monkey ES cell into all three embryonic germ layers in vitro. Feeder cell-free monkey ES cell derivatives or clonally derived ES cells will be subjected to paradigms involving growth factor removal with additions of conditioned medium, extracts of monkey tissues, or precursors of the dopaminergic and cholinergic synthesis pathway. The efficiency of cell type differentiation will be determined by counting dopaminergic and cholinergic cells that will be identified by specific protein or gene markers. This is a revised application that is focused on understanding the directional differentiation of monkey ES cells in vitro into dopaminergic and cholinergic neurons for future transplantation studies with monkey models of Parkinson's or Alzheimer's diseases.

Thesaurus Terms: biological signal transduction, cell communication molecule, cell differentiation, cell growth regulation, embryonic stem cell, neurogenesis choline acetyltransferase, fibroblast growth factor, laminin, membrane transport protein, neurotransmitter receptor, receptor expression, tyrosine 3 monooxygenase tissue /cell culture

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 30-SEP-2002
Project End: 31-AUG-2004
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: MDCN

1R01HD043209-01
Suppression of Breakthrough Bleeding in LNG-IUS Users
$397,500
Brenner, Robert M

Abstract: DESCRIPTION (provided by applicant): The Mirena(c) (Leiras, OY, Finland) is an intrauterine system (IUS) that releases levonorgestrel (LNG) and provides women with highly effective contraception for 5 years. However, serious breakthrough bleeding (BTB) can occur that leads many patients to discontinue treatment. In women using subcutaneous Norplant contraception, BTB can be suppressed by intermittent antiprogestin therapy with mifepristone. NICHD has a new antiprogestin, CDB-2914, that is more potent than mifepristone. The goal of this proposal is to determine whether CDB-2914 can suppress the BTB associated with the LNG-IUS. Preclinical studies will be done first in rhesus macaques fitted with an LNG-IUS and the information gained will be transmitted to Professor Hilary Critchley, University of Edinburgh, who will select a test population of 150 women from a pool of over 400 who are being fitted annually with an LNG-IUS for contraception. The bleeding-suppressive dose and schedule of CDB-2914 that works well in macaques will be adapted for use in women. The work consists of two major aims: Aim 1: to establish an effective, bleeding-suppressive dose schedule of CDB 2914 in macaques, and to assess spatio-temporal expression of bleeding-associated factors in the endometrium. Aim 2: to conduct a randomized, placebo controlled trial to evaluate CDB-2914 suppression of BTB in women being fitted with the LNG-IUS; and for added value, to develop a questionnaire to assess acceptability of the proposed treatment to women. This proposal involves translation of the information gained from basic research with macaques into clinical practice in women within the time frame of the grant. It is essential to conduct the clinical work at the University of Edinburgh, Scotland, UK, because no clinic in the USA has such a large patient population of women being fitted with the LNG-IUS for contraception. The macaque model provides excellent predictability for human studies, and Drs. Brenner and Critchley have published collaboratively on data from macaques and women in several recent papers. The proposal brings basic scientists and clinicians together for a "bench to bedside" approach that will advance women's health and improve contraceptive technology.

Thesaurus Terms: drug adverse effect, endometrium, hemorrhage, hormone inhibitor, human therapy evaluation, levonorgestrel, nondrug contraceptive, progestin, reproductive system disorder chemotherapy clinical trial, dosage, gene expression, nonhuman therapy evaluation, pharmacokinetics, reproductive system pharmacology, women's health British Isles, Macaca mulatta, biopsy, clinical research, female, human subject, microarray technology, morphometry, patient oriented research Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 27-SEP-2002
Project End: 30-JUN-2007
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: ZHD1

1R01HL066118-01A1
Nicotine & Alpha7 nicotinic receptor in lung development
$382,750
Spindel, Eliot R

Abstract: DESCRIPTION (provided by applicant): According to the latest statistics from the CDC in 1999, 12.3% of American women smoked during pregnancy, translating to over 400,000 smoke-exposed infants. Smoking during pregnancy is the largest preventable cause of low birth weight, premature delivery, neonatal morbidity, and mortality. Indeed it has been estimated that 10% of all fetal and neonatal deaths are due to smoking during pregnancy. Perhaps less well appreciated is the recent, evidence that smoking during pregnancy directly and adversely affects lung development as manifested by altered pulmonary function and increased respiratory illness in children born of smoking mothers. Remarkably, how smoking produces these effects is unknown. While the cause of pulmonary damage caused by maternal smoking is likely to be multifactorial, it is the basic hypothesis of this application that part of the effect of maternal smoking on lung is mediated by nicotine transported across the placenta to interact with alpha7 nicotinic receptors in developing lung. Our preliminary evidence indicates 1) that alpha7 nicotinic receptors are highly expressed in developing lung; 2) that prenatal nicotine exposure alters alpha7 nicotinic receptor expression in lung; and 3) that collagen gene expression is markedly up-regulated in areas of altered alpha7. Suggesting that nicotine's effect on collagen is mediated by alpha7 receptors, prenatal nicotine exposure has no effect on collagen gene expression in the lungs of cx7 knockout mice. In exciting preliminary data, nicotine inhibits fibroblast proliferation from cells isolated from wildtype neonatal mouse lung, but has no effect on proliferation of fibroblasts from alpha7 knockout mice. This suggests that some of the growth retardation caused by smoking during pregnancy may be mediated by the interaction of nicotine with alpha7 receptors. In this application, using alpha7 knockout and alpha7 gain of function mice, we propose to first demonstrate a link between the effects of prenatal nicotine exposure and alpha7 nAChR, then using cultured pulmonary fibroblasts and epithelial cells begin to determine the mechanism by which nicotine produces these effects. Based on our preliminary data and epidemiologic data on human infants, we will focus on 3 aspects of smoking's effects on lung development: pulmonary function as measured by active and passive tests, cell growth, and collagen expression. From these studies will come some of the first explanations of the molecular mechanisms that underlie the effects of smoking during pregnancy on lung development. These findings will also potentially point to ways to block some of those effects of smoking during pregnancy as well as assist in fighting smoking during pregnancy.

Thesaurus Terms: drug interaction, embryo /fetus toxicology, embryology, lung, lung injury, nicotine, nicotinic receptor cell proliferation, collagen, drug administration rate /duration, drug administration route, gene expression, placental transfer, receptor expression, respiratory function, tobacco abuse female, gene targeting, laboratory mouse, morphometry, plethysmography, tissue /cell culture, transgenic animal

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-JUL-2002
Project End: 30-JUN-2007
ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG: HED

1R01NS044330-01
Genetically Modified Rhesus Monkeys
$598,114
Brenner, Robert M

Abstract: DESCRIPTION (provided by applicant): Neurogenetic diseases cause tens of thousands of deaths in the United States each year, inflict immeasurable pain and suffering, and consume a substantial portion of scarce healthcare resources. A mouse counterpart for many of these diseases does not exist necessitating the creation and use of new mammalian models. Despite the significant challenges associated with the development of monkey models of neurogenetic diseases, the time is appropriate and the need is compelling. Accordingly, our long-term goal is to produce genetically modified Rhesus monkeys that will serve as models for human neurogenetic diseases. We will focus on three, early-onset, loss of function conditions: Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. We will attempt to establish the paradigm relatively quickly, an objective that can not be met with diseases that require decades to reveal themselves. Because Kallmann's syndrome and Lesch-Nyhan's disease are due to mutations in genes located on the X chromosome (KAL1 and HPRT, respectively), loss of function XY cell mutations require disruption of only one allele. Disruption of the two copies of the autosomal Ataxia Telangiectasia Mutated (ATM) gene, while more difficult, will establish the methods necessary for disrupting autosomal genes in vitro. Our working hypothesis is that gene targeting and somatic cell cloning technology can, in combination, provide the basis for generating a reliable supply of animals that accurately represent human disease. The objective of this application is to create the infrastructure necessary to genetically modify Rhesus monkey cells in culture and to use those cells as donors for nuclear transfer. The resultant viable embryos of the desired genotype can then be transferred into surrogate mothers. Genetically modified Rhesus macaques will result. Such animals should provide a resource for the study of human neurogenetic diseases and serve as pre-clinical models for new experimental treatments including gene and stem cell based therapies.

Thesaurus Terms: Macaca mulatta, biological model, model design /development, neurogenetics, transgenic animal Kallmann's syndrome, Lesch Nyhan syndrome, ataxia telangiectasia, gene expression, genotype, hypoxanthine phosphoribosyltransferase, telomerase gene targeting, nuclear transfer, polymerase chain reaction, site directed mutagenesis, tissue /cell culture

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 15-AUG-2002
Project End: 30-JUN-2007
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: ZRG1

1R13RR017070-01
WORKSHOP/USE OF NONHUMAN PRIMATES/NEUROSCIENCE RESEARCH
$31,658
Ojeda, Sergio R

Fiscal Year: 2002
Department: NONE
Project Start: 01-FEB-1999
Project End: 31-JAN-2004
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: LBPA

1S10RR016747-01
DNA Sequencer (Applied Biosystems 3100)
$149,350
Spindel, Eliot R

Abstract: This abstract is not available.
Thesaurus Terms: There are no thesaurus terms on file for this project.

Fiscal Year: 2002
Department: NONE
Project Start: 01-MAY-2002
Project End: 30-APR-2003
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: ZRG1

2R01HD029186-05A1
Postnatal Development of Ionotropic Glutamate Receptors
$250,425
Urbanski, Henryk F

Abstract: This abstract is not available.
Thesaurus Terms:There are no thesaurus terms on file for this project.

Fiscal Year: 2002
Department: NONE
Project Start: 01-SEP-1993
Project End: 31-MAR-2007
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: BCE

3R01AG019914-01S1
Effect of Aging and Caloric Restriction on Circadian Ph*
$149,350
Urbanski, Henryk F

Abstract: DESCRIPTION (provided by applicant): Human physiology shows strong rhythmic components with peaks and nadirs occurring regularly at specific times of the day. Accumulating evidence suggests that perturbation of the circadian neuroendocrine circuitry may play an important role in several aging-related disorders and may have a major influence on life span. Furthermore, there is growing support for the view that neuroendocrine aging may be caused by oxidative injury, stemming from a progressive overload of a cell's antioxidant capacity. The proposed research will use male rhesus monkeys to examine the mechanism by which caloric restriction can prevent aging-related deterioration of key neuroendocrine circadian rhythms, including DHEAS, cortisol, melatonin and testosterone. We will perform experiments to examine the aging-related progression of circadian dysfunction in ad libitum-fed and age-matched calorie-restricted animals in vivo. This will involve repeated serial blood collections via a catheter-swivel-tether set up, together with concomitant body temperature recordings and actography. In addition, changes in body composition and brain morphology will be assessed non-invasively using DEXA and MRI respectively. Ultimately, the brains of these animals will be examined postmortem to test the hypothesis that caloric restriction protects the aging primate hypothalamus from oxidative injury. Using electron microscopy, we will examine the synaptology of key hypothalamic nuclei involved in mediating circadian neuroendocrine function and use in situ hybridization histochemistry to assess changes in gene expression. We will also use immunohistochemistry to examine loss of specific axonal projections and the associated increase in gliosis. We expect to show that caloric restriction helps to protect hypothalamic nuclei from oxidative injury and, more importantly, that it helps to maintain the integrity of the neural pathway that links the suprachiasmatic nucleus (the central biological clock) to the paraventricular nucleus (the hypothalamic regulator of the adrenal axis). A deeper understanding of aging-related changes in central neuroendocrine circadian circuits of primates and the protective influence of caloric restriction should help to elucidate the mechanism of human aging and help with the development of effective therapies for a wide range of disorders in the elderly.

Thesaurus Terms: aging, caloric dietary content, circadian rhythm, dietary restriction, hypothalamus, neuroprotectant, oxidative stress, suprachiasmatic nucleus antioxidant, cortisol, dehydroepiandrosterone, gene expression, melatonin, morphology, testosterone Macaca mulatta, blood chemistry, computer data analysis, confocal scanning microscopy, immunocytochemistry, in situ hybridization, magnetic resonance imaging, male, organ culture, photon absorptiometry, radioimmunoassay

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-SEP-2001
Project End: 31-AUG-2005
ICD: NATIONAL INSTITUTE ON AGING
IRG: ZAG1

3R21NS041601-01A1S1
Characterization and Differentiation of Monkey ES Cells
$49,999
Pau, K-Y F

Abstract: DESCRIPTION (provided by applicant): The application of embryonic stem (ES) cell therapy for the treatment of human degenerative diseases should be performed in nonhuman primates prior to human trials. The macaque is an ideal animal model for neural transplantation studies because the developmental potential of the grafted cells can be timely and precisely examined postmortem. As a prelude to in vivo studies, the developmental potential and cell lineage differentiation of monkey ES cells must be established in vitro. To this end, we propose to culture and characterize monkey ES cells free of feeder cells before differentiating them into high-percentage cholinergic and dopaminergic neurons, and to determine the pluripotency of monkey ES cells by single cell culture and spontaneously differentiation into cells of all three embryonic germ layers in vitro, thereby addressing the objectives of this PA (PA-99-086/-01-076, NOVEL APPROACHES TO ENHANCE STEM CELL RESEARCH). Aim 1 will characterize two monkey ES cell lines with an XX and XY karyotype that are cultured under feeder cell-free conditions. Rhesus monkey ES cells will be plated on Matrigel- or laminin-coated dishes and cultured in a serum-free medium supplemented with fibroblast growth factors (FGFs), laminin, serum replacement, or conditioned medium from cell cultures to sustain the pluripotency and undifferentiated states. The growth rate, karyotype normalcy, and undifferentiated state will be determined. Aim 2 will directionally differentiate monkey ES cells into dopaminergic and cholinergic neurons, and to differentiate single monkey ES cell into all three embryonic germ layers in vitro. Feeder cell-free monkey ES cell derivatives or clonally derived ES cells will be subjected to paradigms involving growth factor removal with additions of conditioned medium, extracts of monkey tissues, or precursors of the dopaminergic and cholinergic synthesis pathway. The efficiency of cell type differentiation will be determined by counting dopaminergic and cholinergic cells that will be identified by specific protein or gene markers. This is a revised application that is focused on understanding the directional differentiation of monkey ES cells in vitro into dopaminergic and cholinergic neurons for future transplantation studies with monkey models of Parkinson's or Alzheimer's diseases

Thesaurus Terms:There are no thesaurus terms on file for this project.

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 30-SEP-2002
Project End: 31-AUG-2004
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: MDCN

2R01HD029186-05A1
Postnatal Development of Ionotropic Glutamate Receptors
$250,425
Urbanski, Henryk F

Abstract: This abstract is not available.
Thesaurus Terms:There are no thesaurus terms on file for this project.

Fiscal Year: 2002
Department: NONE
Project Start: 01-SEP-1993
Project End: 31-MAR-2007
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: BCE

5D43TW000668-08
INTERNATIONAL TRAINING AND RES. IN POPULATION AND HEALTH
$227,127
Conn, Paul M

Abstract: This research training program is designed to enable NIH grant recipients of the Oregon Health Sciences University (OHSU) to continue to extend the geographic base of research and training efforts to Mexico and Chile, countries in which the dynamics of population growth negatively impacts public health, the environment and economic progress. This program includes pre-doctoral and sabbatical training opportunities in reproductive sciences. Because of the proximity of Mexico to the United States and the substantial length of the common border, problems in this neighboring country influence not only United States border towns but also general patterns of immigration into the U.S. and the politics of American entitlement programs. The advent of the North American Free Trade Agreement (NAFTA) agreement in 1994 and severe economic programs in Mexico makes this program particularly appropriate. A training interaction with Mexico is especially timely now since training opportunities for Mexican nationals are severely limited due to the devaluation of the peso against the dollar to nearly the lowest level on record, and on a political situations that closed the doors of the National University, UNAM, for nearly one year. Likewise, due to the fall of a military dictatorship, Chile is enjoying a period of economic and political stability. Chile offers a unique opportunity due to the significant level of training of its scientists and the recent indication of the Chilean federal government's commitment to science and infrastructure development. We have received letters of cooperation from Mexican and Chilean institutions and will continue to have access to trainees selected from over 300 hospitals and 200 research institutions. The proposed program dove-tails with existing expertise, funding, and the presence of proven mentors and a working program in the area of reproductive sciences. Our previous funding period was extremely productive and consistent with the goal of the program.

Thesaurus Terms:
epidemiology, fertility, health science research, international cooperation, public health, training
Mexico, South America

PORTLAND, OR 97201
Fiscal Year: 2002
Department: NONE
Project Start: 30-SEP-1995
Project End: 30-APR-2005
ICD: FOGARTY INTERNATIONAL CENTER
IRG: ZHD1

1U01AG021382-01
Ovarian Aspects of Caloric Restriction
$378,531
Zelinski-Wooten, Mary B

Abstract: DESCRIPTION (provided by applicant): Caloric restriction (CR) extends the life span, slows aging and retards age-related disease processes in short-lived mammalian species. Reproductive aging encompasses a life-long continuum of follicle depletion in the ovary that leads to decreased fecundity in older women and culminates in menopause, the cessation of ovarian/menstrual cyclicity, and its associated health-related risks. Caloric restriction delays the onset of ovarian follicular loss in rodents. Whether ovarian senescence is likewise suspended during CR in primates is not well understood. Using young and old female rhesus monkeys undergoing acute and long-term CR and their age-matched controls (CON), we propose to assess whether CR alters ovarian aging by determining: 1 ) the patterns and levels of gonadotropin and steroid hormones as well as inhibin-related proteins during spontaneous menstrual cycles and the peri-menopausal period; 2) the responsiveness of somatic cells of the ovarian follicle, i.e. granulosa cells, to exogenous gonadotropin or "fertility" treatment, and resultant follicular growth and maturation; and 3) gene expression in luteinizing granulosa cells and localization of protein factors involved in the pro- or anti-apoptotic (cell death) pathways in the ovarian follicle. Hormonal profiles will be measured in daily samples during 3 consecutive menstrual cycles in all animals, and frequent sampling will be done over a 6-hour period during the early follicular phase of 21 cycles to determine gonadotropin pulsatility in acute CON and CR animals. AII animals will receive recombinant human gonadotropins to stimulate the growth of multiple pre-ovulatory follicles followed by a bolus of hCG to induce peri-ovulatory events. Progesterone production by luteinizing granulosa cells in the presence or absence of hCG in vitro will be measured, and global gene expression will be assessed by microarray technology. Ovarian morphology and protein localization will be examined with histochemical and immunocytochemical analyses in acute CON and CR animals. These studies will provide valuable insight into the potential impact of CR on the mechanisms of ovarian aging in primates.

Thesaurus Terms: aging, caloric dietary content, dietary restriction, ovary age difference, cell proliferation, chorionic gonadotropin, cooperative study, corpus luteum, gene expression, gonadotropin, graafian follicle, inhibin, menopause, menstrual cycle, protein localization, reproductive system pharmacology, steroid hormone Macaca mulatta, animal old age, histochemistry /cytochemistry, human genetic material tag, mature animal, microarray technology, nutrition related tag

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 30-SEP-2002
Project End: 31-AUG-2005
ICD: NATIONAL INSTITUTE ON AGING
IRG: ZAG1

1U24RR018107-01
Establishment Of Specific Pathogen Free Rhesus And Pigta
$1,515,234
Axthelm, Michael K

Abstract: DESCRIPTION (Provided by applicant): Opportunistic human viruses and their simian counterparts are similar in their genetic makeup and induce a similar spectrum of diseases in their immunosuppressed hosts. Experimental lentivirus infections in rhesus macaques are widely recognized as the most import animal model for AIDS-related research and there is an urgent need to expand breeding programs to meet future AIDS vaccine and pathogenesis research program needs. Development of an Indian rhesus macaque breeding colony free of opportunistic viral agents is proposed to enhance the usefulness of this unique resource for studies focused on AIDS-related opportunistic infections. Housing space is proposed to provide a protected environment for this unique Expanded Specific Pathogen Free (ESPF) macaque resource and to facilitate enhanced macaque breeding efforts.

Thesaurus Terms: Macaca mulatta, Macaca nemestrina, animal colony, germ free condition, opportunistic infection AIDS vaccine, Herpesviridae, Retroviridae, cooperative study, genetic strain, simian immunodeficiency virus, virus disease

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 30-SEP-2002
Project End: 31-AUG-2007
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: RIRG

5P51RR000163-43
REGIONAL PRIMATE RESEARCH CENTER - BASE GRANT
$9,789,737 (originally: $9,343,297)
Kohler, Peter O

Abstract: This 5-year renewal for Grant P51 RR00163 includes requests for support of the Center's AIDS-related research programs and improvement and Modernization projects. The application reflects the significant changes that have occurred at the Center since it was last reviewed in 1994, as well as our plans for expanding the use of nonhuman primates (NHPs) as models for human disease. The aims of this application are to: 1) provide the infrastructure support necessary to conduct advanced research for which NHPs are uniquely suited for solutions of human health problems; 2) enhance the Center's resources (scientific expertise, laboratories, animal services and equipment so as to serve as a regional, national and international resource research through support of our unique programs to develop genetically identical animals, to produce SPF animals free of viruses such as herpes B, and to define animal parentage and genotype; and 4) build new research programs utilizing NHPs in functional genomics, aging, gene therapy and vaccine development. These aims facilitate the research programs housed n the research divisions. Research in the Division of Neuroscience focuses n neuroendocrinology, the effects of aging on brain function, etiology of stress-related pathologies and affective disorders, growth factors and lung development, drug addiction and depression, dietary components is involved in research that includes molecular aspects of CMV latency, blood brain barrier dysfunction in AIDS, studies of SIV neurotropism, effects of altered cell tropism on the pathologic potential of type D retrovirus, the role of T and B cell responses in retrovirus infections, an the role of homocysteine in atherosclerosis. The Division of Reproductive Sciences houses projects including nuclear embryos transfer, causes of premature labor, neuroendocrine regulation of the menstrual cycle and prolactin secretion, the role of sex steroids in ovarian function and vascular occlusion, hormonal control of the reproductive tract, and the cell biology of fertilization. Support services for the intra- and extramural research programs are provided by three services divisions. The Division of Administration oversees all of the operations of the Center. The Division of Animal Resources is responsible for the veterinarian and animal care that supports the health and well being of our animal population. The Division of Information Technology and Engineering oversees all of the communications and bioengineering services of the Center.

Thesaurus Terms: Primate, animal colony

Fiscal Year: 2002
Department: NONE
Project Start: 01-MAY-1978
Project End: 30-APR-2004
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: RIRG

5R01AG019914-02
Effect of Aging and Caloric Restriction on Circadian Ph*
$259,289
Urbanski, Henryk F

5R01AI042490-05
Experimental Model for Chorioamnionitis and Prematurity
$278,250
Gravett, Michael G

Abstract: Prematurity is the leading cause of neonatal morbidity and mortality in the United States. Intrauterine infections are an important, and potentially treatable cause of prematurity, and are associated with increased risk of neonatal white matter lesions of the brain and cerebral palsy. However, the mechanisms by which infection leads to prematurity and/or cerebral palsy remain speculative and treatment strategies untested largely because humans cannot be longitudinally studied following infection. We propose to use chronically instrumented pregnant rhesus monkeys at 120-130 day gestation with experimental intrauterine infection, as previously described (Gravett et al, Am J Obstet and Gynecol; 171:1660-1667,1994) to study the temporal and quantitative relationships among infection, cytokines, prostaglandins, steroid hormones, cytokine antagonists, preterm labor, and neonatal white matter lesions of the brain in order to develop effective interventional strategies. After postoperative stabilization in a tether, we will; (1) inoculate Group B Streptococci (GBS) into the amniotic fluid to establish intrauterine infection and preterm labor. Uterine contractility will be continuously monitored and periodic samples of amniotic fluid and maternal and fetal blood (1-4 cc) will be obtained for assays of eicosanoids, steroid hormones, cytokines, matrix metalloproteinases and for microbial studies; (2) utilize antibiotics with and without potent inhibitors of proinflammatory cytokine production (dexamethasone,IL-10) o prostaglandin production (indomethacin) to ascertain the most effective intervention to down-regulate the cytokine/prostaglandin cascade and associated uterine activity; (3) infuse proinflammatory cytokine IL-1beta into the amniotic cavity through indwelling catheters in the absence of infection. Prior to infusion of IL-1beta in the absence of infection, specific novel proinflammatory cytokine inhibitors (IL-1ra and sTNF-R1 PEG) will be used to identify other potentially useful immunomodulators. Samples of the decidua, fetal membranes, tissues, and brain will be obtained at cesarean section for microbiologic, histopathologic studies, immunohistochemistry for cytokines, localization and quantitation of mRNA for cytokines and PGHS-2. Fetal brain will be examined for increased apoptosis associated with white matter lesions. Leukocytes in amniotic fluid and tracheal aspirates will be assessed by flow cytometry Postpartum, the mother will be treated with appropriate antibiotics to eradicate the GBS from the genital tract and returned to the colony. These studies will clarify the pathophysiology of infection-associated preterm labor and will suggest effective interventional strategies.

Thesaurus Terms: antibiotic, antiinflammatory agent, cytokine, microorganism disease chemotherapy, nonhuman therapy evaluation, pregnancy disorder chemotherapy, pregnancy infection, premature labor brain disorder chemotherapy, dexamethasone, disease /disorder model, embryo /fetus chemotherapy, embryo /fetus disorder, immunosuppressive, immunotherapy, indomethacin, interleukin 1, prostaglandin inhibitor Macaca mulatta, Streptococcus agalactiae, embryo /fetus cell /tissue, female, histopathology, immunocytochemistry, neuropathology, newborn animal

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-SEP-1997
Project End: 31-MAY-2006
ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
IRG: HED

5R01CA075922-06
Rhesus Hhv 8 Homologue In Aids Related Malignacies
$652,913
Wong, Scott W

Abstract: Accumulating evidence indicates that human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiological agent associated with the development of Kaposi's sarcoma (KS). In addition to KS, HHV8 is also associated with the development of primary effusion lymphoma (PEL) and some cases of multicentric Castleman's disease (MCD), both B-cell lymphoproliferative disorders (LPD) observed in humans with the acquired immunodeficiency syndrome (AIDS) also presenting with KS. Understanding how HHV8 is involved in these diverse disease manifestations is complicated with the lack of an accessible animal model that recapitulates these diseases. Recently, the investigators and others reported that rhesus macaques harbor a simian herpesvirus that is closely related to HHV8, referred to as rhesus rhadinovirus (RRV). Moreover, experimental inoculation of rhesus macaques with RRV strain 17577 indicates that in macaques previously inoculated with SIVmac239, RRV strain 17577 induces disease manifestations that possess features that resemble KS and MCD. The long-term objectives of this application are to further elucidate how SIV and RRV induce these disease manifestations and to develop this as an animal model to address HHV8-associated disease. To accomplish this, the following specific aims are proposed. Specific Aim 1: Role of immunosuppression in RRV strain 17677-associated disease. Rhesus macaques will be immunosuppressed by either SIVmac239 infection or by iatrogenic agents and inoculated intravenously with RRV strain 17577. Experimentally inoculated macaques will be monitored for viral load by semi-quantitative PCR, changes in leukocyte subsets in peripheral blood and lymph nodes, serological response to RRV, and for clinical signs of RRV-associated disease. Host response to virus infection will be analyzed for inflammatory cytokine expression and activity by RT-PCR, enzyme-linked immunosorbent assays (ELISA) and immunohistochemical staining on samples collected from peripheral blood, lymph node and retroperitoneal fibromatosis (RF) samples from RRV-, SIVmac239- and RRV/SIVmac239-infected samples. Differential expression of activity of inflammatory responses may indicate how RRV/SIVmac239 infection results in the development of RRV-associated disease. Specific Aim 2: Molecular genetic manipulation of the RRV genome. The investigators propose to initiate molecular genetic manipulation of the RRV genome to identify viral determinants of pathogenesis in SIVmac239-infected rhesus macaques. Viral orfs that they believe are important based upon in vitro analysis of infected tissue samples and in vitro cell culture systems will be targeted and nonsense mutations inserted to abrogate the expression of the viral gene product. Specific Aim 3: In vivo pathogenesis of mutant RRVs with defined nonsense mutations in targeted viral orfs. The results from these proposed studies should provide new insights into how RRV and SIV together induce RRV-associated disease, and serve as a means to elucidate the role of HHV8 in HHV8-associated disease.

Thesaurus Terms: Gammaherpesvirinae, Herpesviridae disease, Kaposi's sarcoma, simian AIDS, viral carcinogenesis cytokine, disease /disorder model, gene expression, viremia, virus antigen, virus genetics, virus infection mechanism, virus virus interaction Macaca mulatta, enzyme linked immunosorbent assay, human tissue, immunocytochemistry, polymerase chain reaction

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-JUL-1997
Project End: 30-JUN-2005
ICD: NATIONAL CANCER INSTITUTE
IRG: ZRG1

5R01EY013199-02
Dietary Fatty Acids and Photoreceptor Function
$278,250
Neuringer, Martha D

Abstract: DESCRIPTION (provided by applicant): Docosahexaenoic acid (DHA, 22:6n-3) is a long-chain, highly polyunsaturated n-3 fatty acid. It accounts for about 5O percent of the fatty acids within photoreceptor outer segment disk membranes, the site of phototransduction. Retinal function is altered by changes in retinal membrane DHA content. Rhesus monkeys fed low levels of n-3 fatty acids during development had reduced retinal DHA, impaired visual acuity development and several changes in the electroretinogram (ERG), including prolonged recovery of isolated rod photoreceptor responses to bright, a-wave-saturating flashes. Human infants fed formulas lacking DHA, or containing low levels of its precursors, also showed impairments in the ERG and visual acuity development. In addition, low DHA levels are found in the blood and tissues of many human patients with retinitis pigmentosa and in animal models of retinal degeneration, and dietary DHA is being tested as a possible therapeutic treatment. Despite these indications of DHAs importance in the retina, the nature of the changes in retinal function associated with altered fatty acid composition have not been explored in detail and little is known about their underlying mechanisms. We plan to examine several aspects of retinal function in rhesus monkeys raised on diets with different levels of n-3 fatty acids known to result in widely differing retinal DHA levels. A series of recently developed non-invasive ERG methods will allow us to define effects on phototransduction and photoresponse recovery as well as on rhodopsin regeneration. Specific aims include testing the effects of DHA status on: (1) the activation and deactivation kinetics of isolated rod photoresponses over a wide range of flash intensities; (2) the desensitization of rod responses by background light; and (3) the time-course of dark adaptation over a range of bleaches. In addition, aim 4 will be to test whether any of these alterations in photoreceptor function are reversible after dietary DHA repletion. These studies will provide new information about the modification of retinal function, particularly adaptive processes, by membrane DHA content. Together with in vitro studies of model membranes, these data will help to provide the basis for hypotheses about the underlying processes that are altered by differing retinal fatty acid compositions. They also will contribute to understanding the changes in retinal function found in human infants fed diets lacking DHA or its precursors.

Thesaurus Terms: dark adaptation, dietary lipid, light adaptation, omega 3 fatty acid, visual photoreceptor, visual phototransduction dietary supplement, fluidity, malnutrition, membrane activity, rod cell, visual perception Macaca mulatta, electroretinography, nutrition related tag

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-AUG-2001
Project End: 31-JUL-2004
ICD: NATIONAL EYE INSTITUTE
IRG: VISC

5R01GM045898-12
Srf Operon--Regulation And Role In Genetic Competence
$286,851
Zuber, Peter A

Abstract: DESCRIPTION (adapted from the investigator's abstract): Bacteria possess regulatory networks that sense environmental and metabolic conditions, and respond by generating and transducing signals that affect gene expression. Starvation and high cell density influence the production of virulence factors such as toxins, antibiotics, and degradative enzymes through regulatory networks. They also induce complex cell differentiation processes that give rise to resistant cell types or competent cells that can acquire exogenous DNA. In Bacillus subtilis, the srf operon resides within a regulatory network that governs processes induced by nutrient depletion and high cell density. srf encodes surfactin synthetase, an antibiotic biosynthesis operon, and ComS, a regulatory peptide that controls competence development. The major goal of the project is to understand how srf and comS are regulated and how ComS stimulates competence development. srf is under the control of two converging regulatory pathways. One mediates quorum-sensing control and involves the two-component regulators ComP and ComA; phorphorylated ComA activates srf transcription. The other pathway, involving the Phr extracellular peptide and the SpoOK oligopeptide permease, is activated by starvation and high cell density; the Phr peptide, imported via SpoOK, inhibits the Rap phosphatase that converts ComA to an inactive form, allowing interplay between the two pathways. Activation of phr expression requires the SigmaH form of RNA polymerase, the activity of which is induced by starvation and requires ClpX, an ATP-dependent chaperone. The role of ClpX in the activation of E-SigmaH will be determined by purification and reconstitution of RNA polymerase in vitro for transcription reactions containing purified ClpX proteins. Mutations which suppress the phenotype of a clpX mutant will be characterized to identify factors influencing ClpX-dependent activation of E-SigmaH. Other functions of ClpX in the activation of srf transcription will be identified by testing the effects of clpX comP and clpX spoOK double mutants on srf expression. ComS is required to release ComK, the transcriptional activator of competence gene expression, from the competence inhibitory proteins MecA and ClpC. The ComS-dependent release is thought to rescue ComK from regulated proteolysis. A collection of ComS point mutations will be analyzed to determine the function of ComS in the activation of competence gene expression. These studies will further understanding of the functional links between stress-induced proteins and the regulation of prokaryotic cellular differentiation.

Thesaurus Terms: Bacillus, bacterial genetics, genetic regulation, operon fusion gene, gene mutation, genetic transcription, genetic translation, nucleic acid sequence Escherichia coli, immunoelectron microscopy, molecular cloning

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: BIOCHEM AND MOLECULAR BIOLOGY
Project Start: 01-FEB-1992
Project End: 31-AUG-2004
ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
IRG: MBC

5R01HD006159-30
ENDOCRINE AND PARACRINE RELATIONSHIPS IN PARTURITION
$428,685
NOVY, MILES

Abstract: DESCRIPTION (Adapted from the applicant's abstract): The objectives of this research plan are to clarify the relationships among endocrine, paracrine, and cellular events which culminate in parturition in primates. Aim 1 will establish the separate effects of exogenous ACTH or CRH administered to the fetus or mother at 80+ percent gestation in terms of inducing premature labor as well as describe the changes in the endogenous levels of the same hormones. Aim 2 will describe the presence of androgen and glucocorticoid receptors (ARs, GRs) in rhesus amnion, chorion, decidua, and myometrium at 80 and 100 percent of gestation using immunohistochemistry and ribonuclease protection assay of receptor mRNA. A second part of Aim 2 will use maternal/fetal infusion of androgen agonists and antagonists and a 5-alpha reductase inhibitor to determine the effects of alterations of maternal/fetal androgen levels on gestational length. Aim 3 examines possible mechanisms of progesterone withdrawal by testing for a switch between myometrial progesterone receptor (PR) subtypes (A&B) near term, or a non-genomic mechanism of reduced amniochorion calcium mobilization ("membrane effects") in immune cells. Aim 4 will determine the effects of intraamniotic administration of human IL-8 on parturition.
Thesaurus Terms:
birth, endocrine gland /system, hormone regulation /control mechanism, paracrine, placental hormone adrenocorticotropic hormone, androgen receptor, corticosteroid, corticosteroid receptor, corticotropin releasing factor, interleukin 8, pituitary adrenal axis, premature labor, progesterone receptor Macaca mulatta, RNase protection assay, enzyme linked immunosorbent assay, female, flow cytometry, high performance liquid chromatography, immunocytochemistry, northern blotting, nucleic acid hybridization, polymerase chain reaction, western blotting

Fiscal Year: 2002
Department: NONE
Project Start: 01-JAN-1979
Project End: 31-MAR-2003
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: HED

5R01HD014643-20
CONTROL OF GONADOTROPIN SECRETION DURING LACTATION
$248,102
SMITH, M

Abstract: The central hypothesis of this proposal is that the suppression of GnRH neuronal activity during lactation is due to neural impulses, derived from the suckling stimulus, that alter hypothalamic function and to the change in energy balance associated with milk production. We have identified specific areas in the brainstem that are activated by the suckling stimulus; neurons from each of these areas send projections to the arcuate nucleus of the hypothalamus. We also reported that several neuronal systems in the arcuate nucleus are altered during lactation (increased NPY and AGRP, decreased POMC). These changes are consistent with the chronic hyperphagia of lactation. Our studies showed that NPY projections from the arcuate nucleus makes direct contact with GnRH neurons in the preoptic area and with CRH neurons in the periventricular nucleus (a key site for regulation of food intake). Also, NPY receptors (Y5 subtype) are expressed on GnRH and CRH neurons. Thus, we have established the neuroanatomic framework by which increased NPY activity in the arcuate nucleus could serve as a key element in linking changes in energy balance to the suppression of GnRH neuronal activity during lactation. Another indicator of the change in energy balance is the suppression of leptin during lactation in association with milk production. The proposed experiments expand on these findings and will use three approaches: 1) Neuroanatomical studies will determine the phenotypes of the suckling-activated brainstem neurons that make contact with NPY or POMC neurons in the arcuate nucleus and with GnRH neurons in the preoptic area. 2) Physiological studies will determine if the increase in NPY and the decrease in leptin play functional roles in the suppression of GnRH neuronal activity. 3) Functional genomics will be used to identify additional relevant genes that play key roles in the regulation of NPY and GnRH neurons and in conveying information about the state of energy balance during lactation. The interaction between reproductive function and energy balance during lactation provides a physiological model for studying a number of conditions in women (under-nutrition, anorexia nervosa, bulimia and exercise-induced amenorrhea) that involve a suppression of reproductive function associated with changes in energy balance. All of these conditions have common mechanisms underlying the decrease in GnRH activity.

Thesaurus Terms: gonadotropin releasing factor, hormone regulation /control mechanism, lactation, neuroanatomy, neuron, neuropeptide Y bioenergetics, brain stem, gene expression, hypothalamus, leptin, luteinizing hormone, phenotype, protein structure function, secretion, stimulus /response confocal scanning microscopy, immunocytochemistry, immunofluorescence technique, in situ hybridization, injection /infusion, laboratory rat, microarray technology, radiotracer, tissue /cell culture

Fiscal Year: 2002
Department: NONE
Project Start: 01-DEC-1979
Project End: 28-FEB-2005
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: REN

5R01HD019182-17
HORMONAL CONTROL OF THE FEMALE REPRODUCTIVE TRACT
$321,975
Brenner, Robert M

Abstract: DESCRIPTION: (Adapted from the applicant's abstract) Much remains to be learned about the periodic menstrual sloughing, bleeding and regenerative repair process so characteristic of the primate endometrium. During the previous research period, the investigator discovered an unexpected involvement of vascular endothelial growth factor (VEGF) and its receptors (R) in the menstrual inductive process. Very early in the premenstrual phase, one of the VEGF receptors, VEGFR-2, also known as KDR, was strongly expressed in the stromal cells (not the vascular endothelium) of the upper endometrial zones, the same cell population that expresses most of the matrix metalloproteinases (MMPs). MMPs are enzymes responsible for the tissue destruction and sloughing associated with menstruation. FLT-1, another VEGF receptor, was also transiently upregulated in the glandular cells which also produce an MMP, called matrilysin. Therefore the investigators hypothesize that VEGF acts through KDR and FLT-1 to facilitate MMP expression in the upper endometrial zones during menstrual induction. Hepatocyte growth factor (HGF) was also expressed transiently in the same endometrial stromal cells at the same time. The investigators hypothesize that HGF and VEGF may interact during the LFT to facilitate MMP upregulation. Keratinocyte growth factor (KGF), a growth factor strongly upregulated by P, had strong trophic effects on the spiral arteries, but the KGF receptor was not detectable in the arteries. The arteries do express KDR and FLT-1, so they hypothesize that KGF acts indirectly through the VEGF system to mediate spiral artery growth under P influence. In the current application they propose to explore the interactions between VEGF, HGF and KGF in the primate endometrium within the following specific aims: 1. The VEGF family and MMPs during menstrual induction. 2. VEFG-HGF interactions in MMP regulation. 3. KGF-VEGF interactions in spiral artery growth. 4. HGF and VEGF antagonists during menstruation.

Thesaurus Terms:
fibroblast growth factor, growth factor receptor, hepatocyte growth factor, hormone regulation /control mechanism, menstrual cycle, metalloendopeptidase, progesterone, receptor expression, vascular endothelial growth factor cell cycle, cervix, endometrium, fallopian tube, inhibitor /antagonist, protein protein interaction, receptor binding DNA footprinting, Macaca mulatta, RNase protection assay, female, hormone therapy, immunocytochemistry, morphometry, northern blotting, tissue /cell culture

Fiscal Year: 2002
Department: NONE
Project Start: 01-SEP-1984
Project End: 30-APR-2005
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: REB

5R01HD020869-16
PROGESTERONE RECEPTOR AND ACTION IN THE PRIMATE OVARY
$357,750
STOUFFER, RICHARD

Abstract: DESCRIPTION: (Adapted from the applicant's abstract) The demonstrated activity of progestin to promote ovulation, coupled with the demonstration of progesterone receptor in the luteinizing, ovulating follicle and in the differentiated corpus luteum is compelling evidence for further investigation of the potential actions of progesterone in the ovulating follicle and corpus luteum. This proposal is directed to an investigation of the molecular and cellular events that are steroid/progesterone regulated during follicle rupture and luteinization of the periovulatory follicle, in the maintenance of luteal structure-function in the developed corpus luteum of the nonfertile cycle, and in the rescue of the corpus luteum during early pregnancy. Three treatment protocols will be used in which luteotropic support is sustained via exogenous luteinizing hormone/chorionic gonadotropin during the periovulatory interval, at midluteal phase of the cycle, and in simulated early pregnancy. These protocols are combined with progesterone ablation (using the 3B-hydroxysteroid dehydrogenase inhibitor, Trilostane) and progestin replacement (using the analog, R5020), followed by removal of periovulatory follicle or corpus luteum for analyses. These analyses include indices of tissue remodeling (protease expression, vascularization, cell proliferation), tissue differentiation (cholesterol utilization, steroid genesis, steroid receptor expression), and tissue regression (apoptosis). From these approaches, novel autocrine actions of progesterone in the luteinizing follicle and corpus luteum may be revealed.

Thesaurus Terms:corpus luteum, graafian follicle, hormone regulation /control mechanism, ovary, ovulation, progesterone, progesterone receptor, receptor expression apoptosis, cell proliferation, chorionic gonadotropin, estradiol, luteinizing hormone, menstrual cycle, messenger RNA, pregnancy, prostaglandin, prostaglandin E, prostaglandin F Macaca mulatta, immunocytochemistry, in situ hybridization, northern blotting, polymerase chain reaction, western blotting

5R01HD024870-15
Neural Control Of The Prepubertal Ovary
$383,272
Ojeda, Sergio R

Abstract: DESCRIPTION: (Adapted from the applicant's abstract) This is a renewal application aimed at elucidating some of the basic neuroendocrine and cellular mechanisms overning mammalian ovarian development. During the last period of support we employed a combination of cellular, molecular and genetic approaches to demonstrate the existence of a neurotrophin-mediated regulatory system that is acting at the interface between the endocrine and nervous systems -- contributes to the developmental control of ovarian function. In related studies, we identified a series of additional genes that may belong to the hierarchy of regulatory molecules controlling ovarian folliculogenesis, follicular growth and ovulation. The recognition of these new regulatory components, and the use of genetic approaches to modify the expression of genes in a cell-specific and temporally restricted manner, provides us with a new opportunity to unravel some of the key cell-cell regulatory mechanisms underlying mammalian ovarian development. To initiate this undertaking we propose two sets of studies: The first, to define the physiological importance of NGF and its receptors I follicular growth and ovulation, and their contribution to the etiology of ovarian cystic disease; the other, to elucidate the role that a set of functionally diverse genes found to be differentially expressed in the ovary at two key developmental phases (folliculogenesis and first ovulation) may play in the regulation of these processes. To this end, the following specific aims are proposed: 1. To test the hypothesis that, while required for normal follicular growth, NGF overproduction in endocrine cells of the follicular wall leads to the development of cystic ovarian disease via activation of the low-affinity neurotrophin receptor, p75NGFR. 2. To examine the hypothesis that activation of trkA, the high ffinity tyrosine kinase NGF receptor, in ovarian endocrine cells of mesenchymal origin contributes to the completion of two critical phases in the natural history of the developing ovary, the initiation of preantral follicular development and rupture of the follicular wall at ovulation. 3. To define the role that insulin receptor-related receptor (IRR), an orphan receptor of the insulin receptor family recently found to be co-expressed with trkA in thecal cells of periovulatory follicles, plays in ovulation, and to molecularly identify the gene encoding the IRR ligand. 4. To test the hypothesis that follicular formation requires the temporal and cell-specific coordinated expression of three functionally diverse genes found to be differentially displayed at the time of folliculogenesis; the adhesion molecule Cadherin-11, the protooncogene PTTG, and the transcriptional regulator ENX-1.

Thesaurus Terms: animal puberty, cell differentiation, growth factor receptor, histogenesis, nerve growth factor, neuroendocrine system, neuroregulation, ovary, protein structure function, receptor expression cadherin, developmental genetics, gene expression, graafian follicle, insulin receptor, ovulation, pathologic process, polycystic ovary syndrome, protein tyrosine kinase, protooncogene, transcription factor gene targeting, laboratory rat, transgenic animal

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-FEB-1988
Project End: 31-JAN-2006
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: REB

5R01HD025123-13
Neuroendocrinology Of Puberty And Sexual Development
$369,311
Ojeda, Sergio R

Abstract: This is a renewal application aimed at elucidating the neuroendocrine mechanisms involved in controlling the initiation of mammalian puberty. During the current period of support, our studies have: a) provided evidence for the existence of key signaling molecules utilized by glial cells to regulate the secretory activity of luteinizing hormone releasing hormone (LHRH) neurons, b) unveiled the existence of a higher level of hierarchy in the neuroendocrine cascade that controls the onset of puberty and c) identified a potential new component of the hypothalamic regulatory complex controlling females sexual development. We now propose the use of two different conditional gene targeting approaches to disrupt the function of these newly recognized regulatory molecules in a cell-specific and temporally-restricted manner, and thus, test the hypothesis that they are essential components of the central mechanism controlling the acquisition of female reproductive capacity. To this end, the following specific aims are proposed: 1. To test the hypothesis that an astrocyte-specific, temporally-controlled disruption of erbB-1 receptors, which mediate the actions of transforming growth factor alpha (TGFalpha), delays female sexual maturation by affecting both the gonadal-independent and steroid- dependent activation of LHRH release. 2. To examine the hypothesis that selective disruption of astroglial erbB-2 coreceptors, which are required for amplification of hypothalamic erbB-1-and erbB-4-mediated actions, delays sexual maturation when effected at key phases of LHRH neurosecretory activity. 3. To investigate the hypothesis that selective disruption of astroglial erbB-4 receptors, which mediate the actions of NRGs in hypothalamic astrocytes, results in maturational deficits similar to (or more pronounced than) those caused by the loss of erbB- 1/erbB-2-mediated signaling. 4. To define the role that Nel, a recently identified neuronal protein with EGF-like repeats, may play in the cell-cell communication process underlying the hypothalamic control of sexual development. 5. To test the hypothesis that TTF-1, a member of the Nkx family of homeodomain genes that remains postnatally expressed in discrete hypothalamic regions, is an intrinsic component of both the neuron-to-neuron and glia-to-neuron signaling process controlling the onset of female puberty.

Thesaurus Terms: animal puberty, gonadotropin releasing factor, luteinizing hormone, neuroendocrine system, transforming growth factor astrocyte, developmental genetics, epidermal growth factor, estradiol, gene expression, growth factor receptor, homeobox gene, hormone regulation /control mechanism, hypothalamus, protein tyrosine kinase, receptor expression female, gene targeting, laboratory mouse, laboratory rat, transgenic animal

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-SEP-1990
Project End: 31-MAY-2005
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: BCE

Fiscal Year: 2002
Department: NONE
Project Start: 01-JUL-1985
Project End: 28-FEB-2006
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: REB

5R01HD037131-04
FETAL NICOTINE EXPOSURE EFFECT ON PRIMATE LUNG
$311,273
SPINDEL, ELIOT

Thesaurus Terms:embryo /fetus toxicology, histogenesis, lung, nicotine, respiratory function
biological model, gastrin releasing peptide, nicotinic receptor, receptor expression
Macaca mulatta, immunocytochemistry, in situ hybridization, organ culture, polymerase chain reaction

Fiscal Year: 2002
Department: NONE
Project Start: 01-FEB-1999
Project End: 31-JAN-2004
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: LBPA

5R01MH062677-02
OVARIAN STEROID REGULATION OF SEROTONIN IN PRIMATES
$318,000
BETHEA, CYNTHIA

Abstract: DESCRIPTION (applicant's abstract): The previous interest of this laboratory in the neural regulation of progestin-induced prolactin secretion in primates has evolved into a broader interest in the regulation of serotonin neural function by ovarian steroids. The serotonin neural system projects to nearly every area of the forebrain and serotonin plays a major role in the regulation of numerous autonomic and cognitive neural processes. Thus, understanding the action of ovarian steroids in the serotonin neural system has relevance to many aspects of mental health and function in women. This proposal continues our search, at a cellular and molecular level, for neural targets of progesterone (P) which are unique from the action of estrogen (E) and it initiates studies to determine the mechanism by which E exerts differential effects on the expression of 3 pivotal genes: tryptophan hydroxylase (TPH), the serotonin reuptake transporter (SERT), and the 5-HT1A autoreceptor, in serotonin neurons of macaques. The overall hypothesis is that progesterone (P) has unique, undiscovered, genomic actions in the serotonin neural system which elevate 5-HT neurotransmission. Estrogen (E) is required for the induction and maintenance of nuclear P receptors and E alone changes the expression of pivotal genes related to serotonin synthesis, uptake, and neuronal firing. The molecular actions of E may be mediated by ER-beta and could involve a protein-protein interaction with nuclear factor kappa B (NF-kB). Aim 1 will obtain definitive evidence that addition of P to an E regimen increases serotonin neurotransmission by application of microdialysis and measurement of serotonin in the extracellular compartment of terminal fields in steroid-treated macaques. Aim 2 will determine the functional consequences of previously reported changes in TPH, SERT, and 5-HT1A autoreceptor gene expression in serotonin neurons of macaques treated with E and P. Aim 3 will determine the effect of E and P on degradative mechanisms of serotonin. Gene expression and function of monoamine oxidase (MAO-A) will be determined in the dorsal raphe and hypothalamic termina1 field. Aim 4 will seek the expression of ER-beta and determine if nuclear factor kappa B (NF-kB) is co-expressed and regulated by E or P in serotonin neurons of macaques. Aim 5 will use laser capture to obtain pure populations of serotonin neurons from steroid-treated macaques and amplify their RNA for examination of genes related to phosphorylation events. These experiments will (1) further the hypothesis that E and P increase serotonin neural function and (2) initiate investigations of the mechanism of action of E and P in serotonin neurons.

Thesaurus Terms: estrogen, hormone regulation /control mechanism, neural transmission, ovary, progesterone, serotonin amine oxidase (flavin), gene expression, limbic system, neuron, nuclear factor kappa beta, nuclear receptor, phosphorylation, serotonin receptor, serotonin transporter, tryptophan 2,3 dioxygenase Macaca, animal genetic material tag, immunocytochemistry, microarray technology, microdialysis, molecular cloning, western blotting

Fiscal Year: 2002
Department: NONE
Project Start: 01-FEB-2001
Project End: 30-NOV-2005
ICD: NATIONAL INSTITUTE OF MENTAL HEALTH
IRG: ZRG1

5R01RR016030-02
PROPAGATION OF MONKEY MODELS OF HUMAN DISEASE
$597,946
Wolf, Don P

Abstract: This abstract is not available.
Thesaurus Terms: There are no thesaurus terms on file for this project.

Fiscal Year: 2002
Department: NONE
Project Start: 01-JUL-2001
Project End: 30-JUN-2006
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: RIRG

5R01NS037952-04
Development Of Sexually Dimorphic Forebrain Pathways
$262,554
Simerly, Richard B

Abstract: DESCRIPTION ( Verbatim from the Applicant's Abstract): The long range goal of this work is to clarify the cellular and molecular events that underlie hormonal control of the development of sexually dimorphic neural pathways in the mammalian forebrain. Central to this goal is a clear understanding of how steroid hormones influence the development of connections between subpopulations of neurons that control sex specific behaviors and physiological responses. The proposed project will use the connections of the anteroventral periventricular nucleus of the preoptic region (AVPV) as a model system to study how sex steroid hormones specify sexually dimorphic patterns of afferent and efferent connections. The overall hypothesis is that the higher levels of estradiol present in males acts on the AVPV through the estrogen receptor alpha (ERa) during the first few days of life to differentiate its neurons and promote innervation by neurons of the principal nucleus of the bed nuclei of the stria terminalis (BSTp) while at the same time suppressing formation of projections from the AVPV to neuroendocrine neurons. Axonal labeling and histochemical methods, as well as both in vivo and in vitro experimental models, will be used to test this hypothesis.

Thesaurus Terms: brain /spinal pathway /tract, developmental neurobiology, preoptic area, sex differentiation, thalamus afferent nerve, efferent nerve, estradiol, estrogen receptor, gender difference, hormone regulation /control mechanism laboratory mouse, laboratory rat, tissue /cell culture

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-SEP-1999
Project End: 31-AUG-2003
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: ZRG1

Abstract: This abstract is not available.
Thesaurus Terms: There are no thesaurus terms on file for this project.

Fiscal Year: 2002
Department: NONE
Project Start: 01-JUL-2001
Project End: 30-JUN-2006
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: RIRG

5R37HD019899-18
GONADOTROPIN-RELEASING HORMONE ACTION
$469,749
CONN, PAUL

Abstract: Studies dealing with the biochemical and molecular mechanism of gonadotropin releasing hormone (GnRH) action have served to: (a) identify new clinical and veterinary uses for GnRH and its analogs, (b) bring these uses to fruition through a rational process based on understanding of the mechanism of hormone action, and (c) provide the means for anticipating, understanding, and ameliorating side-effects of the agents. FDA approvals of GnRH agonists for the treatment of prostate cancer, endometriosis, and precocious puberty, as well as for the use of natural sequence GnRH to induce ovulation, and to test the hypothalamic-pituitary-gonadal axis, are examples of the clinical usefulness derived from these fundamental observations. There are multiple advantages to the study of GnRH- stimulation of the gonadotrope that make it facile to collect interpretable data: (a) GnRH stimulation of the gonadotrope cell has clearly defined, specific and measurable endpoints: release of endocrine (and potentially endocrine) substances (LH, FSH, secretogranin II, alpha- subunit of gonadotropin), regulation of target cell sensitivity, regulation of the GnRH receptor, and biosynthesis of released substances. (b)The releasing hormone itself (as well as its agonists and antagonists) can be radioiodinated to high specific activity. (c) Many (>3,000) analogs exist that can be chemically derivatized without loss of biological activity. Antagonists and agonists which bind the receptor with greater affinities than the natural sequence GnRH are available. (d) Virtually all known agonists and antagonists are "pure" in action and metabolically stable agonists are available. The present project is divided into three areas of focus that are detailed in the "Specific Aims" section and form the basis of organization of the "Research Design and Methods" section. The first area will provide information on the structure of the GnRH receptor and early actions following the interaction of the receptor with GnRH and its analogs. At the present time, due to technical difficulties in dealing with the receptor itself, it has not been possible to use standard techniques to purify or even solubilize the receptor for a protracted period. Accordingly, these studies should advance our understanding of the receptor in the mechanism of GnRH action. The second area will provide information on the relationship between the multiple effector mechanisms already implicated in GnRH action with the multiple actions stimulated by the releasing hormone (release of multiple endocrine substances, regulation of target cell responsiveness, biosynthesis, and regulation of receptor number). This is important since considerable confusion remains regarding these relationships. The third area involves understanding the molecular sites of action of activin and inhibin in relation to GnRH action and are significant to understand the actions of these agent in vivo.

Thesaurus Terms: biological signal transduction, gonadotropin releasing factor, hormone receptor, hormone regulation /control mechanism G protein, adenosine diphosphate, calcium, calcium channel, calmodulin, follicle stimulating hormone, inhibin, inositol phosphate, luteinizing hormone, molecular weight, peptide hormone analog, phosphorylation, protein kinase C, receptor binding, ribose phosphate affinity labeling, immunoprecipitation, laboratory rabbit, laboratory rat, radioimmunoassay, tissue /cell culture

Fiscal Year: 2002
Department: NONE
Project Start: 01-APR-1984
Project End: 30-NOV-2003
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: NSS

5U42RR016025-03
Establishment Of Spec Pathogen Free Rhesus Macaque Colon
$970,844
Axthelm, Michael K

Abstract: The projected need for Indian rhesus macaques for AIDS-related research exceeds availability from current domestic breeding programs and there is an urgent need to expand breeding programs for Indian rhesus macaques for future AIDS vaccine and pathogenesis studies. Further, rhesus macaques with defined histocompatibility complex genotypes and known pedigree are becoming increasingly important for research to understand the biologic variation in the immune response. The long-term objective of this application is to expand the Oregon National Primate Center's specific pathogen-free Indian rhesus resource and sufficiently characterize their MHC haplotype to permit selected pedigree breeding for MHC class I alleles useful in AIDS research. The specific aims for accomplishing these objectives include intensively managing a subpopulation of the Center's SPF Indian rhesus macaque breeding colony to maximize production of genetically diverse females to expand the breeding capacity of the colony. Selective breeding of MHC-typed animals will be used to enhance production of future breeder males that are homozygous for the MAMU-A 01 allele, an important allele for assessing virus-specific cell-mediated immune function in simian immunodeficiency virus vaccine models for preventing AIDS virus infection. Breeder males that are homozygous for the MAMU-A 01 allele can be used to efficiently produce large numbers of offspring carrying the desired allele without inbreeding. The breeding colony will be initially typed for eight MHC alleles and managed for the production of MHC-defined offspring of known parentage. New sheltered field cage housing is proposed to protect the animals from infectious agents in the environment.

Thesaurus Terms: Macaca mulatta, animal breeding, animal colony, germ free condition MHC class I antigen, animal care, epizootiology, genotype, major histocompatibility complex, simian immunodeficiency virus

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 30-SEP-2000
Project End: 31-AUG-2005
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG: ZRR1

5U54HD018185-19
Cooperative Research On Infertility In Primates
$1,203,773
Stouffer, Richard L

Abstract: This study from the Oregon National Primate Research Center (ONPRC) establishes a Specialized Cooperative Center (U54) in Reproduction Research that addresses the causes and cures of human infertility disorders as they rate to neural, gonadal and gamete deficits. Each of the four research projects utilizes non-human primates in preclinical trials, and three contain clinical components in an effort to relate new information rapidly to the human situation. The first project, "Effect of Common Life Stresses on Fertility," will test the hypothesis that mild, relatively acute forms of stress (e.g., dieting and psychosocial changes) influence fertility in adult monkeys. Also, data will be generated to determine if success rates in treating women with tubal infertility correlate with patients' stress levels. The second project, "GABAergic Control of LHRH Neuronal Function," will utilize genetic and cellular manipulations to probe the role of GABAergic innervation to the development, migration and function of the LHRH neuronal network. Both Projects have components that focus on potential lesions in the LHRH system in the etiology of infertility. The third project, "Biomedical Basis of Intracytoplasmic Sperm Injection (ICSI," explores whether the molecular and cellular events following ICSI are comparable to natural fertilization. Information from these experiments will be used to test novel strategies for evaluation the quality of microinjected human sperm. The fourth project, "Vasoactive Factors in ART Cycles and Ovarian Hyperstimulation Syndrome (OHSS), " will test the hypothesis that methods used to generate multiple mature follicles/corpora lutea in ART cycles lead to an aberration in ovarian production of vascular endothelial-specific substances that could cause OHSS symptoms. Thus, Projects III and IV attempt to improve methods of diagnosing and treating infertility. These projects will be supported by three core (Assisted Reproductive Technologies or ART, Core A, Imaging & Morphology, Core B; Molecular & Cellular Biology, Core C) laboratories operating in an "open access" formula. The Administrative Core will foster intra- and inter-center cooperation to facilitate basic and clinical research. The U54 Center at ONPRC will be established within a strong interactive, collegial environment that has existed for two decades during prior NICHD Population Center support.

Thesaurus Terms: cooperative study, reproduction

Institution: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2002
Department: NONE
Project Start: 01-SEP-1984
Project End: 31-MAR-2004
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: ZHD1

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