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Grants
Below is a listing of CRS members funded grants. Information on this page will be periodically updated.
Kelly Mayo
PO1 HD21921, National Institute of Child Health and Human Development.
12/01/2003-11/30/08 $7,125,804.00
Director, Kelly Mayo
"FSH directed signaling granulosa cells-role of AKAP".
Abstract: Differentiation of granulosa cells from an immature to a mature phenotype is regulated by FSH-stimulated activation of cAMP-dependent protein kinase (PKA). While some early and many late response genes have been identified downstream of PKA in immature granulosa cells, the signaling pathways beyond PKA which lead to activation of these genes are poorly understood. We have determined in immature cells that FSH-activated PKA directly phosphorylates the nuclear protein histone H3 and that PKA promotes the unique activation of both the p38 and p42/44 mitogen activated protein kinase (MAPK) pathways; these pathways are inhibited by cAMP in most other cells. Activation of PKA in mature granulosa cells (by LH) similarly promotes activation of the p42/44 MAPK pathway and phosphorylation of histone 3, but as shown by others, leads to down-regulation of some of the late response genes activated in immature granulosa cells and up- regulation of other proteins. Recent studies suggest that the cellular location of PKA (a) is a critical determinant for phosphorylation of appropriate target proteins and (b) is regulated by association with A- kinase anchoring proteins (AKAPs). We hypothesize that the unique responses of granulosa cells to PKA, like MAPK activation, and distinct responses between immature versus mature cells are mediated in part by specific expression of one or more AKAPs. In support of this hypothesis, we have demonstrated that FSH promotes the induction of an 80 kDA AKAP which preferentially binds RIIalpha, and that expression of AKAP 80 promotes the redistribution of PKAIIalpha in mature granulosa cells. Aims of this proposal will test the hypotheses that actions of FSH in immature granulosa cells require anchoring of PKA to AKAPs; that the FSH-inducible 80 kDA AKAP is a unique protein which co-localizes with PKAIIalpha in preovulatory granulosa cells; and that AKAP 80 is required for PKA to activate responses characteristic of mature granulosa cells; This basic knowledge of how cAMP/PKA signals in granulosa cells is expected to provide insights towards understanding pathways which regulate ovulation and luteinization and which can translate into safer and more effective treatments of infertility and early pregnancy loss. Thesaurus Terms: binding protein, cell differentiation, follicle stimulating hormone, granulosa cell, hormone regulation /control mechanism, phosphorylation, protein kinase A aromatase, enzyme substrate, gene expression, gene induction /repression, inhibin, mitogen activated protein kinase, progesterone receptor, protein localization, protein sequence expression cloning, female, immunofluorescence technique, laboratory rat, polymerase chain reaction, protein purification, tissue /cell culture, western blotting.
- Administrative Core - Kelly Mayo
- Project I - "Activin regulation of ovarian follicle development", Kelly Mayo/Teresa Woodruff
- Project II - "Non classical estrogen rece;ptor alpha action in the ovary", J. Larry Jameson/Jon Levine
- Project III - "FSH-stimulated signals that regulate follicular maturation", Kelly Mayo
- Core B - Ovarian procurement, processing, and analysis core
Teresa Woodruff
U54 HD041857, National Institute of Child Health and Human Development.
04/23/03-03/31/08 $5,631,278
Director, Teresa Woodruff
"Center for Reproductive Research at Northwestern University: structure-function relationships in reproductive biology".
Abstract: This grant application requests funds to create a Center for Reproductive Research at Northwestern University. The Center will support a multidisciplinary group of scientists who will use innovative approaches toward an understanding of the mechanisms governing normal female fertility. The research focus of the Center will be to understand the structure-function relationships that exist between cells in the ovary and the hormones that regulate follicle maturation. The program is unique in its development of state-of-the-art biomaterials and advanced biophysical and structural approaches to achieve a more comprehensive understanding of ovarian function. The major hypothesis driving the proposed research is that normal follicle development depends upon the appropriate integration of signals derived from cell-cell contact and from the hormones and growth factors that are provided to the follicle structure in a cycle-dependent manner. Four projects will address this central hypothesis using innovative investigative strategies and a cohesive and highly effective partnership between basic biologists, structural biologists, chemical engineers, and clinical investigators. The projects that have been developed specifically for the Center include the derivation of an artificial three-dimensional environment in which individual oocyte-cumulus complexes can grow and to which endocrine factors can be applied; an investigation of the LH receptor and its role in follicular signal transduction pathways; an analysis of the interactions between ovarian co-activators, which are necessary for integrated gene activation and silencing; and the structural relationships between the follicle regulating hormones, inhibin and activin, and their signaling receptors. The rationale for creating such a Center is that elucidating the structure-function relationships between cells within the follicle and the hormones, receptors, and signaling molecules that control ovarian function will greatly advance our understanding of fema le reproductive physiology and thereby directly impact women's health. Thesaurus Terms: cooperative study, female, fertility, ovary, reproduction.
- Project I - "Ovarian-mimetic polymeric scaffolds for the culture of primary ovarian follicles", Lonnie D. Shea/Teresa Woodruff/Ralph Kazer
- Project III - "Transcription factor interactions in reproductive homone gene expression", Kelly Mayo/Ishwar Radhakrishnan
- Project IV - "Structure-function studies of activin and inhibin receptor complexes", Theodore Jardetzky/Teresa Woodruff
- Administrative Core - Teresa Woodruff
Jon Levine
T32 HD07068, National Institute of Child Health and Human Development.
07/01/99-06/30/04 $1,005,116
Director, Jon Levine
"Training Program in Reproductive Biology supporting pre- and postdoctoral fellows in reproductive biology".
Preceptors: Kelly Mayo, Fred Turek, Erv Goldberg, Teresa Woodruff and Catherine Woolley
Abstract: The purpose of this program is to train five predoctoral and three postdoctoral fellows in specific areas of reproductive biology, within the framework of an integrated, multidisciplinary program offering a uniquely broad perspective of the reproductive sciences. Specific areas of training are: (i) Reproductive endocrinology hormonal interactions among the hypothalamus, pituitary, and gonads; molecular and cellular actions of neurohormones, gonadotropins, and gonadal hormones, and control of their secretions, (ii) Cellular, molecular, and hormonal events controlling folliculogenesis and gametogenesis, (iii) Sex determination and reproductive development molecular genetics of sexual differentiation, organizational effects of gonadal steroids, and mechanisms governing sexual maturation, (iv) Pregnancy molecular endocrinology and cell biology of the placenta, and (v) Environmental and metabolic control of reproduction neural mechanisms that integrate energy balance and reproductive processes, and mediate reproductive effects of environmental variables. A broad array of in vivo and in vitro methodologies are available for trainees, including current technologies for investigation at genetic, molecular, cellular, integrative, and behavioral levels. Our ten preceptors are from four departments at Northwestern University; Among them, they hold 12 R01 grants (8 from NICHD), a NICHD-sponsored Program Project Grant, two NICHD-supported U54 Center Grants, and a NICHD-funded Specialized Center of Research. Predoctoral trainees are selected from large, highly qualified pools of graduate students who complete at least one year of study within the programs of preceptors. Postdoctoral fellows are likewise chosen on the basis of their predoctoral work in laboratories of leading investigators in the field. Preceptors in this program have established a strong history of collaboration in their research, and this spirit of interaction continues to permeate the pre- and postdoctoral training arenas. Fellows participate in laboratory research, didactic courses, work-in-progress meetings, a class on ethical scientific conduct, research seminars, journal clubs, a yearly Symposium on Reproductive Biology, and meetings devoted to important professional issues. As a result, our trainees receive intensive training in a specific area of reproductive research, acquire a broad perspective of reproductive biology as a whole, and are exposed to a rich environment of interdisciplinary collaboration. Through administration of this program, we continue to produce highly-trained, successful scientists who carry with them a continuing interest in an integrated, multi-level approach to the study of reproduction.
Andrea F. Dunaif
P50 HD044405, National Institute of Child Health and Human Development.
27/09/02-31/7/07 $
Director, Andrea Dunaif
"Specialized Center of Research on Genes, Androgens and Intrauterine Environment in PCOS".
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of premenopausal women, and results in male hormone excess and irregular periods. It is the leading cause of hormonally-related infertility and is a major risk factor for type 2 diabetes mellitus in both adolescent and young adult women. It also often associated with obesity and risk factors for cardiovascular disease. When left untreated, it can result in endometrial cancer. PCOS has a substantial negative impact on quality of life because of the disorder's multisystem morbidities. Clearly, PCOS is an overarching women's health problem affecting women throughout their life span. Furthermore, since type 2 diabetes and obesity have now reached epidemic proportions in the US, and cardiovascular disease remains the leading cause of death in women, PCOS plays a key role in the foremost causes of death and disability in US women.
The cause of PCOS remains unknown. However, we have already found a gene region that is associated with the condition. The goals of this SCOR are to identify the gene in this region and to determine how this gene results in reproductive abnormalities and increased risk for diabetes. We have evidence that one way this gene may result in these problems is by causing a female baby to produce male hormones during pregnancy. To investigate this possibility, we will determine whether we can produce features of PCOS in animals by giving them male hormones before they are born. These studies will provide a better understanding of how PCOS develops. These studies also promise to identify a gene for PCOS, which likely also causes diabetes and obesity. This research will not only lead to new therapies but also to genetic testing for and prevention of PCOS.
- Project 1 - Genes, Intrauterine Environment and PCOS. Andrea Dunaif, MD, Principal Investigator.
This project will determine whether the PCOS genetic marker is associated with metabolic defects that increase risk for diabetes in women with PCOS. It will also determine whether the female babies of women with PCOS who have this genetic marker have evidence for increased male hormone production during pregnancy and/or are smaller than normal
- Project 2. Identification of Chromosome 19 PCOS Susceptibility Gene. Margrit Urbanek, Ph.D., Principal Investigator.
This project will identify the PCOS susceptibility gene or genetic element that is linked to the marker for PCOS already identified on chromosome 19.
- Project 3. Fetal Androgen Induces Ovarian, LH and §-Cell Defects. David H. Abbott, Ph.D., Principal Investigator.
This project will directly determine whether male hormone exposure before birth can result in many of the reproductive and metabolic features of PCOS after the monkey is born.
- Project 4. Neuroendocrine Actions of Androgens in Females. Jon E. Levine, Ph.D., Principal Investigator.
This project will determine exactly how male hormone exposure during pregnancy can alter reproductive function and metabolism. The project will investigate whether this effect can be explained by alterations cell channels that regulate reproductive hormone release in the brain and insulin secretion in the pancreas. These studies will be performed in rats and in monkeys.
James L. Jameson
U01 HD043425-02, National Institute of Child Health and Human Development.
09/27/02-06/30/07 $
James L. Jameson, P.I.
Identify Sex Determination Genees by ENU Mutagenesis
Abstract: Sex determination in mammals is governed by a series of genetic switches that influence cell fate and differentiation during critical periods of development. Remarkably, the primordial fetal gonad is bipotential and the precursor gonadal cells can develop along either a male (testis) or female (ovary) pathway, depending on which genes are expressed. The main goal of this project is to identify key genes that regulate gonadal development and phenotypic sex. To this end, the investigators propose to screen mice for sex-reversal, manifest as XY phenotypic females or as XX phenotypic males, taking advantage of the existing Northwestern University Genome Wide ENU Mutagenesis Center. The specific aims of this project are: Aim 1: To screen progeny of ENU-mutagenized mice for sex reversal. Mice will be characterized genetically for the presence or absence of the Y-chromosomal Sry gone. At age 21 days, they will be classified as phenotypically male or female. This screen will include at least 10,000 mice per year. Aim 2: To characterize the gonadal phenotype of mice with sex-reversal. Morphologic, hormonal, histologic, and developmental analyses will be used to characterize the gonadal (testis and ovary) defects associated with sexreversal. Functional analyses will assess spermatogenesis in males or ovulation in females. These initial studies will be followed by more detailed characterizations of altered gene and protein expression using in situ hybridization, quantitative RT-PCR, immunohistology, and western blot studies. Microarray analyses will be used to identify altered genetic pathways, particularly during key stages of gonadal development. Aim 3: To perpetuate germline transmission of mutations associated with sex-reversal and gonadal dysgenesis and to map the genetic locus of the defect. Aim 4: To act as a national resource for mouse mutants by providing access to phenotypic screening analyses "online". In addition to listing identified phenotypes online, putative mutants that are heritable will be cryopreserved and made available to the scientific community directly from the Center and through arrangements with an established national distribution center. Gonadal development provides an excellent opportunity to identify genes involved in differential organogenesis. In addition to providing new information about basic mechanisms that regulate gonad development, these studies are also likely to enhance our understanding of gonadal dysgenesis and infertility in humans. Thesaurus Terms: gene expression, genetic mapping, genetic screening, mammalian embryology, mutant, reproductive development, sex chromosome, sex determination animal breeding, cooperative study, genotype, gonad, gonad disorder, information dissemination, online computer, phenotype biotechnology, cryopreservation, cytogenetics, ethanol, in situ hybridization, laboratory mouse, microarray technology, polymerase chain reaction, western blotting.
Jon Levine
U54 HD041859
04/28/03- $
Jon Levine, P.I.
Core-Ligand Assay
Abstract: In this U54 Center Grant application, we propose to expand the capacity of an existing Ligand Assay Core at Northwestern University (Jon E. Levine, Director) to meet the assay needs of the U54 Chicago Center for Reproductive Research (CCRR) Center Grant Investigators. The Ligand Assay Core will provide direct assay service, training, consultation, and access to equipment and supplies for hormone and neuropeptide measurements required by projects of Core users. The CCRR Projects 1-4 will all access the Core, and will compensate the Core in proportion to their usage according to a standardized chargeback system. The specific aims of the Ligand Assay Core are as follows: 1. To enhance the cost-effectiveness of hormone and neurotransmitter measurements required by Core users in approved projects. 2. To maintain stringent and consistent quality control standards in all assays. 3. To make available assay procedures that would otherwise be impractical and/or not feasible for use by individual investigators. 4. To develop new assay methods to enhance the projects of Core users. Thesaurus Terms: biomedical facility, hormone, ligand, measurement, neuropeptide, neurotransmitter cooperative study, hormone regulation /control mechanism, reproduction, technology /technique development, training enzyme linked immunosorbent assay, radioimmunoassay.
Erwin Goldberg
D43-TW00654-09 Fogarty International Center (subcontract from University of Virginia)
9/1/99-4/30/04 $ 167,600
Erwin Goldberg, P.I.
Research Training in Reproduction for Asian Fellows
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