Elastic Fiber Homeostasis in the Vaginal Wall

描述(由申请人提供)：盆底疾病影响多达三分之一的成年女性。最常见的盆底疾病之一是盆腔器官脱垂，即盆腔器官(膀胱、阴道、宫颈和子宫)通过阴道开口突出。多达11%的女性在有生之年接受过盆腔器官脱垂或尿失禁手术，在美国，每年有超过22.5万例盆腔器官脱垂住院手术，估计每年直接医疗费用超过10亿美元。尽管盆腔器官脱垂的发生有多种机制的假说，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，阴道出生和年龄是发生盆腔器官脱垂的两个主要危险因素。妊娠、分娩和衰老对盆底支持机制的具体影响尚未确定。最近，有报道编码赖氨酰氧化酶样1(LOXL1)基因零突变的小鼠发生盆腔器官脱垂。我们发现，FblnS基因敲除的小鼠也会出现严重的泌尿生殖系统脱垂。有趣的是，LOXL1和纤毛蛋白-5是参与合成和组装成细胞外基质的弹性纤维的蛋白质，这两种小鼠模型在分娩后都会出现严重的阴道壁脱垂。通过初步研究，我们发现两种降解弹性蛋白的酶在盆腔器官脱垂妇女的阴道肌肉中的转录显著增加。这些发现，加上这两个动物模型的结果，为这一赠款申请的总体假设提供了基础，即盆腔器官的支持是通过阴道壁中弹性纤维的合成/组装和降解之间的微妙平衡来维持的。我们认为，对阴道弹性组织及其支持结构的破坏会导致阴道支持的丧失。功能丧失的程度取决于最初损伤的程度、调节酶损伤的天然蛋白酶抑制剂的存在以及弹性蛋白纤维进行修复的能力。在这一应用中，我们建议(1)确定怀孕、分娩和产后期间阴道和盆底支撑性结缔组织中弹性纤维的稳态调节；(2)确定类固醇激素和机械创伤对盆腔器官脱垂和弹性纤维的形成和降解的影响；(3)检验产后合成fiblin-5对于阴道分娩后阴道壁的恢复至关重要的假设。

DESCRIPTION (provided by applicant): Pelvic floor disorders affect up to one-third of adult women. One of the most prevalent pelvic floor disorders is pelvic organ prolapse, a condition in which the pelvic organs (bladder, vagina, cervix and uterus) herniate through the vaginal opening. Up to 11% of women have surgery for pelvic organ prolapse or urinary incontinence in their lifetime and more than 225,000 inpatient surgical procedures for pelvic organ prolapse are performed per year in the United States at an estimated annual direct medical cost of over one billion dollars. Although multiple mechanisms have been hypothesized to contribute to the development of pelvic organ prolapse, none fully explain the origin and natural history of this process. Epidemiologic studies indicate that vaginal birth and aging are the two major risk factors for developing pelvic organ prolapse. The specific effects of pregnancy and parturition and aging on pelvic floor support mechanisms have not been identified. Recently, it was reported that mice with null mutations in the gene encoding lysyl oxidase like 1 (LOXL1) develop pelvic organ prolapse. We discovered that fibulin-5 (FblnS) knockout mice also develop severe urogenital prolapse. Interestingly, LOXL1 and fibulin-5 are proteins involved in synthesis and assembly of elastic fibers into the extracellular matrix, and both mouse models develop severe prolapse of the vaginal wall after giving birth. By way of preliminary studies, we find that transcripts of two enzymes that degrade elastin are increased significantly in the vaginal muscularis of women with pelvic organ prolapse. These findings, together with results from these two animal models, provide the foundation of the overall hypothesis of this grant application, namely that pelvic organ support is maintained by a delicate balance between the synthesis/assembly and degradation of elastic fibers in the vaginal wall. We propose that damage to the elastic tissue of the vagina and its supporting structures leads to loss of vaginal support. The degree of functional loss depends on the extent of initial injury, presence of natural protease inhibitors that modulate enzymatic damage, and the ability of elastin fibers to undergo repair. In this application, we propose (1) to determine the regulation of elastic fiber homeostasis in the vagina and supportive connective tissues of the pelvic floor during pregnancy, parturition, and the postpartum time period; (2) To determine the impact of steroid hormones and mechanical trauma on pelvic organ prolapse and elastic fiber formation and degradation; and (3) to test the hypothesis that postpartum synthesis of fibulin-5 is crucial for recovery of the vaginal wall from vaginal childbirth.