Center for Reproductive Research at Northwestern University

描述(申请人提供)：此申请请求继续支持西北大学生殖研究中心(CRR)及其目标，以帮助更全面地了解女性生育和不孕不育。我们中心的目的是从卵泡单位的结构-功能关系和调节卵泡单位的激素的角度来探讨卵泡的动力学。CRR最初建议的目的是通过召集工程、生物物理学和结构生物学专家以及生殖内分泌学家和临床研究人员，促进将基本的生物、生化和生物物理研究成果转移到临床护理中。我们探索了全卵泡结构与其对内分泌激素和旁分泌作用因子(抑制素和激活素)的感知和适当反应能力之间的关系，并对这些机制如何在生物物理上进行了重要的新观察。我们在原子水平上解决了四种主要的激素结构，以及与DNA结合的转录因子的结构。我们还开发了一种体外卵泡成熟系统，支持未成熟卵泡的生长、卵母细胞成熟和健康活体后代的出生。从所有方面来看，该中心的头四年在将工作从基础生殖生物学转变为生物物理学和生物材料到床边方面取得了丰硕成果。为今后五年的工作提出的项目是创新的，并再次利用结构-功能办法侧重于生殖科学中的主要问题。我们的科学家和临床研究人员作为一个高效的团队工作，以确保及时、双向地将信息从临床问题转移到工作台和背部。为了实现我们的目标，提出了四个项目。众所周知，生育力和卵母细胞质量随着年龄的增长而下降，来自老年女性的卵母细胞经常出现异常的减数分裂纺锤体，包括染色体排列异常、微管基质组成异常和非整倍体。Lonnie Shea和他的团队(项目I)开发了一种体外卵泡成熟系统，这是一个探索与年龄相关的卵母细胞健康的有吸引力的模型。他们将检验这一假设，即卵母细胞异常是由于全卵泡复合体缺乏协调生长而产生的。Kelly Mayo和Ishwar Radhakrishnan(项目II)将继续他们对转录因子相互作用的探索，这些转录因子相互作用指导颗粒细胞中激素依赖的基因表达。具体地说，他们将询问SF-1和LRH-1核受体如何与cAMP依赖因子CREB和卵巢因子GATA-4和GATA-6一起在分子水平上调节抑制素-a亚单位基因的表达。项目III由泰德·贾德茨基领导，他正在研究具有调节结合蛋白的复合体中转化生长因子-β超家族配体的原子结构。他对控制卵泡发育的卵母细胞来源的GDF-9和BMP-15特别感兴趣。最后，项目IV将研究结构刚性与卵泡功能的关系，这是Teresa Woodruff和Andrea Dunaif的合作项目。通过将基本的生化、生物材料和生物物理方法与医学相结合，我们将继续走在生殖生物学结构-功能关系的新发现的前沿。此外，我们的每一个持续项目都重申了我们的承诺，即将我们的调查结果转化为床边的成果，从而为妇女的整体健康做出贡献。

DESCRIPTION (provided by applicant): This application requests continuing support for the Center for Reproductive Research (CRR) at Northwestern University and its goal 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 intent of the original CRR proposal was to facilitate the transfer 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. We explored 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 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 I) developed an in vitro follicle maturation system, an 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 Radhakrishnan (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-a 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 III is led by Ted Jardetzky, who is studying the atomic structure of TGF-¿ 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 structural rigidity to follicular function and is 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.