ROLE OF A GONADAL FSH BINDING COMPETITOR IN FSH ACTION

这项研究的长期目标是检验FSH的假设 受体结合竞争对手(FRBC)可以调节 FSH，因此是控制正常的 性腺的发育、生理和病理生理功能。 这里提出的研究的直接焦点是净化和 鉴定最先在卵泡液中发现的58,000 mW FRBC 通过其与FSH受体和抗血清的结合以及其生物学作用 在体外作为促卵泡刺激素激动剂。此外，FRBC具有抗原性 与阿尔法前体蛋白(58，00 mW)的生物化学相关 抑制素亚单位，也起源于性腺，这表明有可能 FRBC翻译后加工调控对FSH的生物调控作用 以一种新的方式作用于性腺FSH受体。 具体目标1涉及进一步纯化和鉴定FRBC， 确认生物活性，并进行微测序以确认两者之间的关系 从FRBC到α抑制素前体。特异性抗肿瘤单抗 将提高FRBC的不同区域以提高纯度，以及 允许对FRBC或其片段进行免疫化学检测 目标。 具体目标2将探索FRBC的解剖分布以及 FRBC合成、加工和分泌的激素调节 利用原代培养的性腺细胞负责产生和 正在分泌FRBC。 特定目标3使用来自目标1的抗体和FRBC，其特征是 目的2建立血清和卵泡液中FRBC的特异性检测方法 在患有FSH相关生殖障碍的患者中。 这些研究的结果应该1)证实局部FSH的存在 调控体系，2)为生物化学和生物化学研究提供探针 FRBC的生理作用，3)阐明FRBC的调节机制 FRBC的翻译后加工，4)探索令人兴奋的 FRBC、FSH激动剂与α-抑制素的相互关系 负责抑制FSH水平，以及5)评估FRBC的作用 在人类生殖生理学中，尤指在控制配子发生方面 以及FRBC在卵巢早熟等疾病状态中的潜在作用 失败了。

The long term goal of this research is to test the hypothesis that FSH receptor binding competitors (FRBC) can regulate the biological action of FSH, and are therefore essential components in the control of normal developmental, physiologic, and patholophysiologic functions of the gonad. The immediate focus of the studies proposed here is to purify and characterize a 58,000 MW FRBC that was first identified in follicular fluid by its binding to FSH receptors and antisera, and by its biological action as an FSH agonist in vitro. Furthermore, FRBC is antigenically and biochemically related to the precursor protein (58,00 MW) of the alpha inhibin subunit, also of gonadal origin, suggesting the possibility that regulation of FRBC posttranslational processing can modulate FSH biological action at the gonadal FSH receptor in a novel way. Specific Aim 1 involves further purification and characterization of FRBC, confirmation of bioactivity, and microsequencing to affirm the relationship of FRBC to alpha inhibin precursor. Specific monoclonal antibodies to different regions of FRBC will be raised to improve purification, and permit immunochemical detection of FRBC or its fragments in subsequent aims. Specific Aim 2 will explore the anatomical distribution of FRBC, as well as the hormonal regulation of synthesis, processing and secretion of FRBC using primary cultures of gonadal cells responsible for producing and secreting FRBC. Specific Aim 3 uses antibodies and FRBC from Aim 1 that are characterized in Aim 2 to develop specific assays for FRBC in serum and follicular fluid in patients with FSH-related reproductive disorders. Results from these studies should 1) confirm the existence of a local FSH regulatory system, 2) provide probes for studying the biochemistry and physiological role of FRBC, 3) elucidate regulatory mechanisms for posttranslational processing of FRBC, 4) explore the exciting interrelationship between FRBC, and FSH agonist, and alpha inhibin, which is responsible for suppressing FSH levels, and 5) evaluate the role of FRBC in human reproductive physiology, especially in control of gametogenesis and a potential role of FRBCs in disease states such as premature ovarian failure.