Project Abstract

The goal of this project is to contribute to a more comprehensive understanding of female fertility and infertility.  The purpose of our center is to explore ovarian follicle dynamics from the perspective of structure-function relationships of the follicle unit and the hormones that regulate it.  The benchmark of this program is the facilitation of basic biological, biochemical and biophysical findings to clinical care by bringing experts in engineering, biophysics and structural biology together with reproductive endocrinologists and clinical investigators.  This model has been used to explore the relationship between the holo-follicular structure and its ability to sense and respond appropriately to endocrine hormones and paracrine acting factors (inhibin and activin) and made significant new observations about how these mechanisms are regulated biophysically.  We have solved four major hormone structures at the atomic level and the structure of a transcription factor bound to DNA.  We also developed an in vitro follicle maturation system that supports immature follicle growth, oocyte maturation and the birth of live, healthy offspring.  By all measures, the first four years of this center have been productive and effective in translating the work from basic reproductive biology to biophysics, and biomaterials to the bedside.  The projects proposed for the next five years of work are innovative and again focus on major questions in reproductive science using a structure function approach.  Our scientists and clinical investigators work as a highly effective team to ensure the timely, bidirectional transfer of information from clinical problem to the bench and back.  To accomplish our goals, four projects are proposed.  It is known that fertility and oocyte quality diminish with age and oocytes from older women frequently have abnormal meiotic spindles, including abnormal chromosome alignment and microtubular matrix composition and aneuploidy.  Lonnie Shea and team (Project 1) developed an in vitro follicle maturation system, and attractive model for exploring age-related oocyte health.  They will test the hypothesis that oocyte abnormalities arise from lack of coordinated growth of the holo-follicular complex.  Kelly Mayo and Ishwar Radhkrishnan (Project II) will continue their exploration of transcription factor interactions that direct hormone-dependent gene expression in the granulosa cell.  Specifically they will ask how SF-1 and LRH-1 nuclear receptors regulate inhibin α-subunit gene expression at the molecular level in conjunction with the camp-dependent factor CREB and the ovarian factors GATA-4 and GATA-6.  Project II is led by Ted Jardetzky, who is studying the atomic structure of TGF-β superfamily ligands in complex with regulating binding proteins.  He is specifically interested in oocyte-derived GDF-9 and BMP-15, which control follicle development.  Finally, Project IV will examine the relationship of structure rigidity to follicular function and is a collaboration between Teresa Woodruff and Andrea Dunaif.  By combining basic biochemical, biomaterial, and biophysical approaches with medicine, we will remain at the forefront of new discoveries in the structure-function relationships of reproductive biology.  Moreover, each of our continuing projects reaffirms our commitment to translate our findings to the bedside, and thereby contribute to the overall health of women.

This application requests support to establish a BIRCWH Program at Northwestern University titled, Career Development in Women’s Health (CDWH).  This program will be used to develop a group of independent, tenure track scientists with backgrounds in clinical medicine or basic science disciplines whose research will address high priority areas relevant to women’s health.  We have identified five focus areas that have been historically strong within Northwestern and that are fundamental to the understanding and treatment of women’s health and disease – differences in cardiovascular disease risk; ovarian biology, obstetrical and gynecological disorders; sex differences in sleep and rheumatology and osteoporosis.  In order to develop expertise outside the Ob-Gyn specialty, faculty members who have interdisciplinary training in basic reproductive science and gender-specific disease research must be cultivated.  Northwestern has a longstanding and rich tradition of interdisciplinary excellence in the reproductive sciences and in disorders that affect women, providing a strong foundation upon which the CDWH program will be developed.  In achieving our goal, the Career Development in Women’s Health Program will create a focused curriculum, provide strong mentorship and engaged faculty development activities.  The junior faculty trained through this program will be in the vanguard of women’s health research scholarship and it is anticipated that training will expand to an ever-widening group of clinicians and investigators.  The program at Northwestern University is robust, timely and rigorous.  Three key ingredients drive this application and will underlie the success of the candidates: high quality research programs, high expectations and a robust training environment.  The CDWH program at Northwestern University is dedicated to these criteria and to the next generation of clinical investigators and translational scientists who will improve health and allay disease in women and men.