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Protease regulation and integrity of connective tissues of the pelvic floor

盆底结缔组织的蛋白酶调节和完整性

基本信息

批准号：
8291898
负责人：
RUTH A WORD
金额：
$ 31.65万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-17 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291898
关键词：
Acids Address Age Aging Animal Model Animals Applications Grants Arginine Biochemical Birth Chemicals Childbirth Collagen Fiber Connective Tissue Data Defect Deterioration Development Down-Regulation Elastic Fiber Epidemiologic Studies Estrogens Gelatinase B Generations Glycine Human Injury Integrin Binding Integrins Knockout Mice Lead Maintenance Menopause Messenger RNA Metalloproteases Mus Mutate Natural History Omi serine protease Organ Pathogenesis Pelvic floor structure Pelvis Peptide Hydrolases Play Postpartum Period Process Protease Inhibitor Proteins Ptosis Reactive Oxygen Species Regulation Risk Factors Role Serine Protease Stretching Stromal Cells Structure Testing Tissues Up-Regulation Vagina Vaginal Prolapses Vaginal delivery procedure Withdrawal Woman age effect fibulin functional loss human MADHIP protein in vivo inhibitor/antagonist knowledge of results mesotrypsin mutant pregnant prevent public health relevance repaired therapeutic development

项目摘要

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.)

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出现盆腔器官脱垂。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。公共卫生关系：在本申请中，我们将确定是否蛋白酶激活的结缔组织的骨盆底是至关重要的发展盆腔器官脱垂。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有助于制定治疗策略，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。）