Protease regulation and integrity of connective tissues of the pelvic floor

描述(申请人提供)：盆腔器官脱垂的发生有多种机制，但没有一种机制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、年龄增长和绝经是主要的危险因素。然而，分娩、衰老和更年期对盆底支撑性结构的具体影响尚不清楚。这种认识上的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害，也无法改善衰老对盆腔器官支持能力恶化的影响。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。除了弹性纤维缺陷外，初步研究结果表明，阴道壁蛋白水解酶活性升高在盆腔器官脱垂的发病机制中是必要的和关键的过程，而基质金属蛋白酶-9起主要作用。在这项赠款申请中，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)阐明基质金属蛋白酶-9在盆底结缔组织中的调节机制；以及(Iii)识别、表征和确定两种潜在的在脱垂的阴道壁中高表达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制定治疗策略，以预防或消除与分娩相关的盆底损伤以及与年龄和更年期相关的盆腔器官支持丧失。 公共卫生相关性：在这项应用中，我们将确定盆底结缔组织中的蛋白酶激活是否对盆腔器官脱垂的发展至关重要。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制定治疗策略，以预防或消除与分娩相关的盆底损伤以及与年龄和更年期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.)