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Collagenolysis and Elastolysis in Urinary Incontinence

尿失禁中的胶原蛋白溶解和弹性组织溶解

基本信息

批准号：
7455855
负责人：
BERTHA CHEN
金额：
$ 30.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7455855
关键词：
Age Aging Area Biological Assay Biopsy Collagen Complement Factor B Cultured Cells Development Elastases Elastin Elements Endopeptidases Enzymes Estradiol Estrogens Etiology Event Extracellular Matrix Fibroblasts Functional disorder Gene Expression Genetic Transcription Goals Gonadal Steroid Hormones Growth Factor Health Hormonal Change In Vitro Incontinence Investigation Leukocyte Elastase Luteal Phase Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mediating Medical Menstrual cycle Metabolism Microarray Analysis Molecular Operative Surgical Procedures Organ Pancreatic Elastase Pattern Pelvis Peptide Hydrolases Peptides Phase Polymerase Chain Reaction Postmenopause Premenopause Prevalence Progesterone Prophylactic treatment Protein C Inhibitor Proteins Proteolysis Ptosis RNA Rate Relaxin Reverse Transcription Role Serine Protease Stress Stress Urinary Incontinence Structure Therapeutic Intervention Tissue Inhibitor of Metalloproteinases Tissue Sample Tissues Transforming Growth Factors Trypsin United States Urinary Incontinence Vagina Western Blotting Woman collagenase deprivation disability inhibitor/antagonist lifetime risk mRNA Expression protein expression reproductive urinary

项目摘要

DESCRIPTION (provided by applicant): Urinary incontinence is a major health problem in the United States, resulting in an 11% lifetime risk of surgery for women with incontinence and/or prolapse. The molecular pathophysiology is poorly understood, inhibiting the development of medical prophylaxis or therapy for this growing area of disability. Collagen and elastin are major supporting elements of pelvic structures. Thus, expression of collagenases, elastases and their inhibitors controls proteolysis of the extracellular matrix and may negatively impact urinary function. We hypothesize that stress urinary incontinence (SUI) results from abnormal pelvic collagen and elastin metabolism as a function of differential expression of the matrix metalloproteinases (MMPs) and elastases and their respective protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) and A-1 anti-trypsin. First, we propose to investigate expression of both the proteolytic enzymes and their inhibitors in vaginal wall tissue isolated from women with SUI and continent women during the follicular and luteal phases of the menstrual cycle using quantitative-competitive reverse transcription polymerase chain reaction (QC-RT-PCR), Western blot, immunohistochemical analysis, and zymography. Second, we will compare the expression of MMPs and TIMPs as well as neutrophil elastase and A-1 anti-trypsin in vaginal tissue samples from continent and incontinent postmenopausal women to determine the effect of estrogen deprivation on RNA and protein expression as well as on collagen and elastin proteolytic activity. In addition, we will compare broad patterns of gene expression between continent and incontinent women using microarray analysis. Third, to assess the role of growth factors in the etiology of urinary dysfunction, we will examine relaxin and transforming growth factor-B (TGF-B) modulation of both collagenolysis and elastolysis in cultured fibroblasts derived from premenopausal continent and incontinent women. Because urinary dysfunction develops as women age, our fourth goal is to examine the ability of 17-B estradiol and progesterone to alter in vitro expression of the ratio of MMPs/TIMPs and total elastase activity/A-1 anti-trypsin in vaginal fibroblast cultures. Two-thirds of the burden of urinary incontinence is borne by women with prevalence rates of 14-41%. Our goal is to identify specific pathophysiologic changes related to reproductive events and aging which underlie the development of SUI as a first step to identifying potential targets for therapeutic intervention.

描述（由申请人提供）：尿失禁是美国的一个主要健康问题，导致患有尿失禁和/或脱垂的女性终生接受手术的风险为 11%。人们对分子病理生理学知之甚少，这阻碍了针对这一日益严重的残疾领域的医学预防或治疗的发展。胶原蛋白和弹性蛋白是骨盆结构的主要支撑元素。因此，胶原酶、弹性蛋白酶及其抑制剂的表达控制细胞外基质的蛋白水解，并可能对泌尿功能产生负面影响。我们假设压力性尿失禁 (SUI) 是由于骨盆胶原蛋白和弹性蛋白代谢异常所致，是基质金属蛋白酶 (MMP) 和弹性蛋白酶及其各自的蛋白质抑制剂、金属蛋白酶组织抑制剂 (TIMP) 和 A-1 抗胰蛋白酶差异表达的函数。首先，我们建议使用定量竞争性逆转录聚合酶链反应（QC-RT-PCR）、蛋白质印迹、免疫组织化学分析和酶谱分析，研究从 SUI 女性和节制女性在月经周期的卵泡期和黄体期分离的阴道壁组织中蛋白水解酶及其抑制剂的表达。其次，我们将比较来自节制和失禁绝经后妇女的阴道组织样本中 MMP 和 TIMP 以及中性粒细胞弹性蛋白酶和 A-1 抗胰蛋白酶的表达，以确定雌激素剥夺对 RNA 和蛋白质表达以及胶原蛋白和弹性蛋白蛋白水解活性的影响。此外，我们将使用微阵列分析比较失禁女性和失禁女性之间基因表达的广泛模式。第三，为了评估生长因子在泌尿功能障碍病因学中的作用，我们将检查松弛素和转化生长因子-B (TGF-B) 对来自绝经前节制和失禁妇女的培养成纤维细胞中胶原蛋白溶解和弹性组织溶解的调节作用。由于泌尿功能障碍会随着女性年龄的增长而出现，因此我们的第四个目标是检查 17-B 雌二醇和黄体酮改变阴道成纤维细胞培养物中 MMP/TIMP 比率和总弹性蛋白酶活性/A-1 抗胰蛋白酶的体外表达的能力。三分之二的尿失禁负担由女性承担，患病率为 14-41%。我们的目标是确定与生殖事件和衰老相关的特定病理生理变化，这些变化是 SUI 发展的基础，作为确定治疗干预潜在目标的第一步。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bench to bedside: clinical opportunities for microarray analysis.

从实验室到临床：微阵列分析的临床机会。

DOI：
10.1016/s0015-0282(03)00727-1
发表时间：
2003
期刊：
Fertility and sterility
影响因子：
6.7
作者：
Polan,MaryLake;Warrington,JanetA;Chen,Bertha;Mahadevappa,Mamatha;Wang,Hongbo;Wen,Yan
通讯作者：
Wen,Yan

Expression of apoptotic factors in vaginal tissues from women with urogenital prolapse.

DOI：
10.1002/nau.21127
发表时间：
2011-11
期刊：
Neurourology and urodynamics
影响因子：
2
作者：
Wen Y;Ho JY;Polan ML;Chen B
通讯作者：
Chen B

Transforming growth interacting factor expression in leiomyoma compared with myometrium.

与子宫肌瘤相比，平滑肌瘤中转化生长相互作用因子的表达。

DOI：
10.1016/j.fertnstert.2009.05.001
发表时间：
2010
期刊：
Fertility and sterility
影响因子：
6.7
作者：
Yen-PingHo,Jason;Man,WengChi;Wen,Yan;Polan,MaryLake;Shih-ChuHo,Esther;Chen,Bertha
通讯作者：
Chen,Bertha

Elastin metabolism in pelvic tissues: Is it modulated by reproductive hormones?