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：
8470671
负责人：
RUTH A WORD
金额：
$ 30.06万
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/8470671
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.

描述（由申请人提供）：已经假设多种机制有助于骨盆器官脱垂的发展，但没有一个充分解释该过程的起源和自然历史。流行病学研究表明，阴道出生，衰老和更年期是主要危险因素。然而，尚不清楚分娩，衰老和更年期对骨盆底的支撑性结构的具体影响。我们的知识差距导致无法制定预防策略，以减少分娩过程中对这些组织的损害，或者改善衰老对骨盆器官支持恶化的影响。与弹性纤维组装和合成有关的蛋白质缺陷的动物模型会发展出骨盆器官脱垂。除弹性纤维缺陷外，通过初步研究获得的结果表明，增加阴道壁蛋白酶活性是骨盆器官脱垂发病机理的必要和关键过程，并且MMP-9起主要作用。在此赠款应用中，我们将（i）检验以下假设：骨盆底的结缔组织中基质蛋白酶激活有助于骨盆器官脱垂的进展；（ii）阐明在骨盆底的结缔组织中调节MMP-9的机制；（iii）识别，表征和确定调节在脱垂的阴道壁中高度表达的两个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骨盆器官支持的重要问题。可以预料，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骨盆底损伤以及与年龄相关的年龄相关的骨盆器官支撑损失。