Center for Reproductive Research at Northwestern University

西北大学生殖研究中心

• 批准号: 7932571
• 负责人: Teresa K Woodruff
• 金额: $ 22.07万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932571
• 关键词: Center; Reproductive; Research; Northwestern; University

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.

描述（由申请人提供）： 本申请要求继续支持西北大学生殖研究中心（CRR）及其目标，以促进对女性生育力和不孕症的更全面的了解。我们中心的目的是从卵泡单位和调节它的激素的结构-功能关系的角度探索卵巢卵泡动力学。最初的CRR提案的目的是通过将工程学、生物物理学和结构生物学专家与生殖内分泌学家和临床研究者聚集在一起，促进基础生物学、生物化学和生物物理学研究结果向临床护理的转移。我们探索了全卵泡结构与其感知和适当响应内分泌激素和旁分泌作用因子（Bisobin和activin）的能力之间的关系，并对这些机制如何进行生物学调节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和与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，支持未成熟卵泡生长，卵母细胞成熟和活的健康后代的出生。通过各种措施，该中心的前四年在将工作从基础生殖生物学转化为生物物理学和生物材料到床边方面是富有成效的。为今后五年的工作提出的项目具有创新性，并再次使用结构-功能方法侧重于生殖科学的主要问题。我们的科学家和临床研究人员作为一个高效的团队工作，以确保信息从临床问题到实验室的及时、双向传输。为了实现我们的目标，我们提出了四个项目。众所周知，生育力和卵母细胞质量随着年龄的增长而下降，老年妇女的卵母细胞经常具有异常的减数分裂纺锤体，包括异常的染色体排列和微管基质组成以及非整倍性。Lonnie Shea和团队（项目I）开发了一种体外卵泡成熟系统，这是一种探索与年龄相关的卵母细胞健康的有吸引力的模型。他们将检验卵母细胞异常是由于缺乏完整卵泡复合体的协调生长而引起的假设。 Kelly马约和Ishwar Radhakrishnan（项目II）将继续探索转录因子的相互作用，指导颗粒细胞中的蛋白依赖性基因表达。具体而言，他们将研究SF-1和LRH-1核受体如何在分子水平上与cAMP依赖因子CREB和卵巢因子加塔-4和加塔-6一起调节BRA亚基基因表达。项目III由Ted Jardetzky领导，他正在研究TGF-β超家族配体与调节结合蛋白复合的原子结构。他特别感兴趣的是卵母细胞衍生的GDF-9和BMP-15，它们控制卵泡发育。最后，项目四将研究结构刚性与卵泡功能的关系，这是Teresa Woodruff和Andrea Dunaif之间的合作。通过将基本的生物化学，生物材料和生物物理方法与医学相结合，我们将保持在生殖生物学结构-功能关系新发现的最前沿。此外，我们的每一个持续项目都重申了我们致力于将我们的研究结果转化为床边，从而为妇女的整体健康做出贡献。