Ovarian Primordial Follicle Development

描述(由申请人提供)：建议的研究旨在更好地了解控制原始卵泡发育的机制。这一过程对于建立和维持雌性生殖是必不可少的。原始卵泡发育包括原始卵泡组装的初始事件和随后原始卵泡向初级卵泡转变的事件。原始卵泡组装的过程与原始卵泡向初级卵泡转变的过程不同，这两个过程都将在拟议的研究中进行研究。当地产生的卵巢物质和激素调节这些过程的方式尤其令人感兴趣。以前的研究和初步研究表明，原始卵泡发育和随后的卵泡发生的控制似乎是由涉及膜细胞、颗粒细胞和卵母细胞的特定旁分泌因子的局部产生和作用所介导的。初步研究表明，类固醇激素(即雌激素和孕酮)在原始卵泡组装的启动过程中起着关键作用。初步研究还表明，原始卵泡向初级卵泡的转变需要卵母细胞、颗粒细胞和囊膜前体细胞之间的整合相互作用，包括KIT配体(KL)、碱性成纤维细胞生长因子(BFGF)、白血病抑制因子(LIF)、角质形成细胞生长因子(KGF)和骨形态发生蛋白-4(BMP4)。一般的假设是激素影响旁分泌生长因子介导的卵巢体细胞和卵母细胞之间的相互作用，以控制原始卵泡的组装和发育。激素和旁分泌生长因子之间的相互作用为控制原始卵泡的发育提供了有效的机制。预计这些细胞相互作用的异常将影响女性的生育能力、更年期的开始，并促进诸如卵巢早衰等病理生理。实验方法包括以下具体目的：1)阐明激素和旁分泌生长因子对原始卵泡组装的调控。2)阐明原始卵泡向初级卵泡转化的激素和生长因子调控。3)阐明调节原始卵泡发育的特定因子的生理意义。这些特定目标的完成将扩展先前的观察，并提供对生长因子介导的细胞-细胞相互作用在调节原始卵泡发育中的作用的洞察。研究的关键发育阶段包括原始卵泡组装的诱导和原始卵泡向初级卵泡的转变。预计特定的细胞-细胞相互作用将在这些发育阶段之间发生变化。激素对生长因子及其受体的不同作用在卵泡发育的后期具有重要作用，但在原始卵泡发育过程中仍有待研究。观察有望提供对原始卵泡发育的分子和细胞控制的洞察。公共卫生相关性：获得的信息将用于了解青春期和更年期的开始，并为未来可能设计的卵巢异常状况的诊断程序和治疗方法提供洞察，如卵巢早衰(POF)和各种形式的女性不孕症。未来实验的一个例子是确定在目前研究中建立的任何生长因子和/或受体库中是否存在突变(S)，作为卵巢早衰等疾病的潜在原因因素。

DESCRIPTION (provided by applicant): The proposed research is directed toward developing a better understanding of the mechanisms that control primordial follicle development. This process is essential for the establishment and maintenance of female reproduction. Primordial follicle development involves the initial event of primordial follicle assembly and the subsequent event of primordial to primary follicle transition. The process involved in primordial follicle assembly is distinct from that of primordial to primary follicle transition and both will be investigated in the proposed research. The manners by which locally produced ovarian substances and hormones regulate these processes are of particular interest. Previous research and preliminary studies have demonstrated that the control of primordial follicle development and subsequent folliculogenesis appears to be mediated by the local production and action of specific paracrine factors involving theca cells, granulosa cells, and the oocyte. Preliminary studies have shown that steroid hormones (i.e. estrogen and progesterone) play a critical role in the onset of primordial follicle assembly. Preliminary studies also demonstrate that primordial to primary follicle transition requires integrated interactions between the oocyte, granulosa cells and precursor theca cells involving kit ligand (KL), basic fibroblast growth factor (bFGF), leukemia inhibitory factor (LIF), keratinocyte growth factor (KGF) and bone morphogenic protein-4 (BMP4). "THE GENERAL HYPOTHESIS TESTED IS THAT HORMONES INFLUENCE THE PARACRINE GROWTH FACTOR MEDIATED INTERACTIONS BETWEEN THE OVARIAN SOMATIC CELLS AND THE OOCYTE TO CONTROL PRIMORDIAL FOLLICLE ASSEMBLY AND DEVELOPMENT". Interactions between hormones and paracrine growth factors provide an efficient mechanism to control primordial follicle development. It is anticipated that abnormalities in these cellular interactions will influence female fertility, menopause onset and promote pathophysiologies such as premature ovarian failure. The experimental approach consists of the following specific aims: 1) Elucidate the hormonal and paracrine growth factor control of primordial follicle assembly. 2) Elucidate the hormonal and growth factor control of the primordial to primary follicle transition. 3) Elucidate the physiological importance of specific factors that mediate primordial follicle development. Completion of these specific aims will extend previous observations and provide insight into the role of growth factor mediated cell-cell interactions in regulating primordial follicle development. The critical developmental periods to be examined include the induction of primordial follicle assembly and the primordial to primary follicle transition. It is anticipated that the specific cell-cell interactions will change between these developmental periods. The differential effects of hormones on growth factors and relevant receptors have a critical role in later stages of follicle development, but remain to be determined in primordial follicle development. Observations are anticipated to provide insight into the molecular and cellular control of primordial follicle development. PUBLIC HEALTH RELEVANCE: The information obtained will be used to understand the onset of puberty and menopause, as well as provide insight into the potential future design of diagnostic procedures and therapeutic treatments for abnormal ovarian conditions such as premature ovarian failure (POF) and forms of female infertility. An example of a future experiment proposed is to determine if mutation(s) exist in any of the repertoire of growth factors and/or receptors established in the current study as potential causal factors for disease states such as premature ovarian failure.