Functional Analysis of SMAD Signaling in Oocytes

描述（由申请人提供）：卵母细胞-颗粒细胞通讯在卵子发生过程中的重要性已被广泛接受。TGF-β超家族成员是卵母细胞-颗粒细胞通讯的重要介质，但这些配体对卵母细胞的直接作用尚不清楚。TGF-β配体通过磷酸化激活靶细胞中的SMAD蛋白。激活的SMAD（SMAD 2/3和1/5/9）结合SMAD 4并易位到细胞核，在那里它们调节核功能。基于对Smad 4基因在卵母细胞中无功能的突变动物的初步分析，本项目验证了以下假设：（1）卵母细胞中Smad 4缺失导致卵泡发育增加;（2）Smad 4突变卵母细胞比对照卵母细胞具有更高的生物活性。总之，这两个目标的结果将为影响卵母细胞发育的机制提供有价值的见解，并可能允许开发干预措施以改善卵母细胞质量和卵巢功能。 公共卫生相关性：拟议的研究活动将增加我们对卵巢功能，卵泡和卵母细胞发育的理解。这些知识将提高我们治疗女性生殖缺陷相关问题的能力，包括不孕症，卵巢早衰和月经周期不规则。

DESCRIPTION (provided by applicant): The importance of oocyte-granulosa cell communication throughout oogenesis is well accepted. Members of the TGF-beta superfamily are important mediators of oocyte-granulosa cell communication, but the direct effect of these ligands on the oocyte is unclear. TGF-beta ligands activate SMAD proteins in target cells through phosphorylation. Activated SMADs (SMAD2/3 and 1/5/9) bind SMAD4 and translocate to the nucleus where they regulate nuclear functions. Based on preliminary analysis of mutant animals were the Smad4 gene is non-functional in oocytes, the present project tests the hypotheses that (1) Smad4 deletion in oocytes causes increased follicular development and (2) Smad4 mutant oocytes are more bioactive than control oocytes. Together, results from these two aims will provide valuable insight into mechanisms that affect oocyte development and may allow for development of interventions to improve oocyte quality and ovarian function. PUBLIC HEALTH RELEVANCE: The proposed research activities will increase our understanding of ovarian function, follicular and oocyte development. This knowledge will improve our ability to treat problems associated with defects in female reproduction, including infertility, premature ovarian failure and irregular menstrual cycles.