Ovarian Primordial Follicle Development

描述（由申请人提供）：拟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女性生殖至关重要。原始卵泡发育包括原始卵泡组装的初始事件和随后的原始卵泡向初级卵泡转变的事件。原始卵泡组装的过程不同于原始卵泡向初级卵泡过渡的过程，这两个过程都将在拟议的研究中进行研究。局部产生的卵巢物质和激素调节这些过程的方式特别令人感兴趣。先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特定的旁分泌因子的局部生产和行动，涉及卵泡膜细胞，颗粒细胞和卵母细胞介导的。初步研究表明，类固醇激素（即雌激素和孕激素）在原始卵泡组装的开始中起关键作用。初步研究还表明，原始卵泡到初级卵泡的转变需要卵母细胞、颗粒细胞和前体卵泡膜细胞之间的整合相互作用，涉及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（BMP-4）。“测试的一般假设是激素影响卵巢体细胞和卵母细胞之间的旁分泌生长因子介导的相互作用，以控制初级卵泡组装和发育”。激素和旁分泌生长因子之间的相互作用提供了控制原始卵泡发育的有效机制。预期这些细胞相互作用的异常将影响女性生育力、绝经期开始并促进病理生理学，如卵巢早衰。本实验的主要目的是：1）阐明激素和旁分泌生长因子对原始卵泡组装的调控作用。2)阐明激素和生长因子对原始卵泡向初级卵泡转变的控制。3)阐明介导原始卵泡发育的特定因子的生理重要性。这些特定目标的完成将扩展以前的观察，并提供深入了解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。要检查的关键发育期包括诱导原始卵泡组装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时期之间发生变化。激素对生长因子和相关受体的不同作用在卵泡发育的后期阶段具有关键作用，但在原始卵泡发育中仍有待确定。观察结果预计提供洞察的原始卵泡发育的分子和细胞控制。公共卫生相关性：所获得的信息将用于了解青春期和绝经期的开始，以及提供对异常卵巢状况（如卵巢早衰（POF）和女性不孕症）的诊断程序和治疗方法的潜在未来设计的见解。提出的未来实验的一个例子是确定在当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，作为疾病状态如卵巢早衰的潜在因果因素。

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.