MOLECULAR MECHANISMS OF CORPUS CAVERNOSUM FIBROSIS

描述(改编自申请者摘要)：勃起功能障碍 在1800万至3000万美国男性中不同程度地发生。近期 治疗方面的进展，一直基于阐明 勃起组织(如小梁平滑肌)的生理机制 放松一下。与之密切相关的小梁平滑肌细胞 在收缩能力上，也合成结缔组织。他们已经证明了 骨小梁平滑肌与勃起组织胶原蛋白的临界比例为 是正常勃起功能所必需的。他们进一步表明， 小体结缔组织含量升高损害整个勃起组织 肿胀时的“消耗性”，干扰经下小静脉 闭塞，导致静脉渗漏。继发性血管性阳萎 结构改变引起的静脉闭塞功能障碍是常见的 勃起功能障碍和导致药理学的主要病理生理学 治疗失败和需要插入阴茎假体。其中一个 勃起生理方面研究最少的是勃起生理的机制(S) 小梁平滑肌调节结缔组织合成和 退化。转化生长因子-β(TGF)是多效性的 诱导结缔组织合成的细胞因子 软组织纤维化。他们已经证明人类的海绵体 表达转化生长因子。他们已经培育出一块人类海绵体的平滑肌肉 保持细胞功能和结构元素的细胞培养模型 结缔组织蛋白。在该模型中，转化生长因子可诱导胶原合成。 前列腺素E_1、福司可林、异丙肾上腺素可抑制这种合成 以及硝普钠，这是一种提高环核苷酸水平的药物。 他们建议测试在这个模型中胶原的合成和降解是否 受改变环核苷酸水平的物质调节。使用这个 模型中，他们将：(1)研究转化生长因子诱导的胶原合成和 降解，(2)确定环核苷酸提升剂的效果 对转化生长因子诱导的胶原合成的影响；(3)研究转化生长因子和 环核苷酸增高剂对转化生长因子和前列腺素E合成和表达的影响 它们的感受器。骨小梁平滑肌的研究现状 收缩能力导致了治疗勃起的创新治疗方法 功能障碍。预计人体胶原蛋白的研究将导致 新的药物预防疗法以恢复和/或保存 功能性小梁平滑肌内容物，维持勃起功能。

DESCRIPTION (Adapted from the Applicant's Abstract): Erectile dysfunction occurs in varying degrees in 18 - 30 million American men. Recent therapeutic advances, have been based on research that elucidated the physiologic mechanisms of erectile tissue (e.g. trabecular smooth muscle) relaxation. The trabecular smooth muscle cell, which is intimately involved in contractility, also synthesizes connective tissue. They have shown that a critical ratio of trabecular smooth muscle to erectile tissue collagen is required for normal erectile function. They have further shown that elevated corporal connective tissue content impairs overall erectile tissue "expendability" during tumescence, interfering with sub-tunical venule occlusion, resulting in venous leakage. Vasculogenic impotence secondary to veno-occlusive dysfunction from structural changes is a common cause of erectile impairment and a major pathophysiology resulting in pharmacologic treatment failures and need for penile prosthesis insertion. One of the least studied aspects of erectile physiology is the mechanism(s) by which trabecular smooth muscle regulates connective tissue synthesis and degradation. Transforming growth factor-beta (TGF) is a pleiotropic cytokine which induces connective tissue synthesis and has been implicated in soft tissue fibrosis. They have shown that human corpus cavernosum expresses TGF. They have developed a human corpus cavernosum smooth muscle cell culture model which maintains functional and structural elements of connective tissue proteins. TGF induces collagen synthesis in this model. This synthesis was suppressed by prostaglandin E1, forskolin, isoproterenol and sodium nitroprusside, agents which elevate cyclic nucleotide levels. They propose to test if collagen synthesis and degradation in this model is regulated by substances which alter cyclic nucleotide levels. Using this model, they will: (1) investigate TGF- induced collagen synthesis and degradation, (2) determine the effects of cyclic nucleotide elevating agents on TGF-induced collagen synthesis and (3) investigate the effects of TGF and cyclic nucleotide elevating agents on TGF and PGE synthesis and expression of their receptors. Previous research on trabecular smooth muscle contractility has led to innovative therapeutic approaches to treat erectile dysfunction. It is anticipated that corporal collagen research will lead to novel pharmacologic prophylactic therapies to restore and/or preserve a functional trabecular smooth muscle content and maintain erectile potency.