Elastic Fiber Homeostasis in the Vaginal Wall

描述（由申请人提供）：骨盆底疾病影响多达三分之一的成年女性。盆腔器官脱垂是最常见的盆底疾病之一，是盆腔器官（膀胱、阴道、宫颈和子宫）通过阴道口疝出的一种疾病。高达11%的女性在一生中接受过盆腔器官脱垂或尿失禁的手术，在美国，每年有超过225,000例盆腔器官脱垂的住院手术，估计每年的直接医疗费用超过10亿美元。尽管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，阴道分娩和衰老是发生盆腔器官脱垂的两个主要危险因素。妊娠、分娩和衰老对骨盆底支撑机制的具体影响尚未确定。最近，有报道称编码赖氨酸氧化酶样1 （LOXL1）基因零突变的小鼠发生盆腔器官脱垂。我们发现，纤维蛋白-5 （FblnS）敲除小鼠也会出现严重的泌尿生殖脱垂。有趣的是，LOXL1和纤维蛋白-5是参与弹性纤维合成和组装到细胞外基质的蛋白质，两种小鼠模型在分娩后都出现了严重的阴道壁脱垂。通过初步研究，我们发现降解弹性蛋白的两种酶的转录本在盆腔器官脱垂的女性阴道肌层中显著增加。这些发现，连同这两个动物模型的结果，为本基金申请的总体假设提供了基础，即盆腔器官支持是由阴道壁弹性纤维的合成/组装和降解之间的微妙平衡维持的。我们认为阴道弹性组织及其支撑结构的损伤会导致阴道支撑的丧失。功能丧失的程度取决于初始损伤的程度、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。在本应用中，我们建议(1)确定妊娠、分娩和产后期间阴道和盆底支持性结缔组织中弹性纤维稳态的调节；(2)确定类固醇激素和机械损伤对盆腔器官脱垂及弹性纤维形成和降解的影响；(3)验证产后纤维蛋白-5的合成对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.