Protease regulation and integrity of connective tissues of the pelvic floor

描述（由申请人提供）：已经假设多种机制有助于盆腔器官脱垂的发展，但没有一种机制能够完全解释该过程的起源和自然史。流行病学研究表明，阴道分娩、衰老和绝经是主要的危险因素。然而，分娩、衰老和绝经对骨盆底支撑结构的具体影响尚不清楚。我们知识上的这一差距导致我们无法制定预防性策略来减少分娩期间对这些组织的损伤，或改善衰老对盆腔器官支持恶化的影响。参与弹性纤维组装和合成的蛋白质缺陷的动物模型会发生盆腔器官脱垂。除了弹性纤维缺陷之外，通过初步研究获得的结果表明，阴道壁蛋白酶活性增加是盆腔器官脱垂发病机制中的必要和关键过程，并且MMP-9起主要作用。在这项资助申请中，我们将（i）检验骨盆底结缔组织中基质蛋白酶激活有助于骨盆器官脱垂进展的假设;（ii）阐明MMP-9在骨盆底结缔组织中调节的机制;和（iii）鉴定、表征和确定在脱垂阴道壁中高度表达的两种潜在的新型丝氨酸蛋白酶的调节。拟议的研究将回答有关维持盆腔器官支持的重要问题。预计了解这些基本机制将导致治疗策略的发展，以预防或消除分娩相关的骨盆底损伤和年龄和绝经相关的骨盆器官支持的丧失。

DESCRIPTION (provided by applicant): Multiple mechanisms have been hypothesized to contribute to the development of pelvic organ prolapse, but none fully explain the origin and natural history of this process. Epidemiologic studies indicate that vaginal birth, aging, and menopause are major risk factors. The specific impact of childbirth, aging, and menopause on the supportive structures of the pelvic floor, however, is not known. This gap in our knowledge results in an inability to develop preventative strategies to reduce damage to these tissues during childbirth or to ameliorate the effects of aging on deterioration of pelvic organ support. Animal models with defects in proteins involved in elastic fiber assembly and synthesis develop pelvic organ prolapse. In addition to elastic fiber defects, results obtained by way of preliminary studies suggest that increased vaginal wall protease activity is a necessary and crucial process in the pathogenesis of pelvic organ prolapse, and that MMP-9 plays a major role. In this grant application, we will (i) test the hypothesis that matrix protease activation in connective tissues of the pelvic floor contributes to the progression of pelvic organ prolapse; (ii) elucidate the mechanisms by which MMP-9 is regulated in connective tissues of the pelvic floor; and, (iii) identify, characterize, and determine the regulation of two potential novel serine proteases highly expressed in the prolapsed vaginal wall. The proposed studies will answer important questions regarding maintenance of pelvic organ support. It is anticipated that understanding these basic mechanisms will lead to the development of therapeutic strategies to prevent or abrogate childbirth-related pelvic floor injury and age- and menopause-related loss of pelvic organ support.