Protease regulation and integrity of connective tissues of the pelvic floor

描述（由申请人提供）：多种机制被假设有助于盆腔器官脱垂的发展，但没有一个能完全解释这一过程的起源和自然历史。流行病学研究表明，阴道分娩、衰老和更年期是主要的危险因素。然而，分娩、衰老和更年期对骨盆底支撑结构的具体影响尚不清楚。这种知识上的差距导致我们无法制定预防策略来减少分娩时对这些组织的损害，也无法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有缺陷的动物模型会发生盆腔器官脱垂。除了弹性纤维缺陷外，初步研究结果表明阴道壁蛋白酶活性升高是盆腔器官脱垂发病的必要和关键过程，其中MMP-9起主要作用。在这项拨款申请中，我们将(i)检验盆底结缔组织中基质蛋白酶激活有助于盆腔器官脱垂进展的假设；（ii）阐明MMP-9在盆底结缔组织中的调节机制；（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控。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，以预防或消除与分娩相关的盆底损伤以及与年龄和绝经相关的盆腔器官支持丧失。

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. PUBLIC HEALTH RELEVANCE: In this application, we will determine if protease activation in connective tissues of the pelvic floor is crucial for the development of pelvic organ prolapse. 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.)