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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017907-06
Application #
6934518
Study Section
Special Emphasis Panel (ZRG1-UKGD (01))
Program Officer
Bellino, Francis
Project Start
2000-03-15
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
6
Fiscal Year
2005
Total Cost
$317,366
Indirect Cost
Name
Stanford University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Wen, Yan; Whitin, John; Yu, Tom et al. (2012) Identification of protein marker in vaginal wall tissues of women with stress urinary incontinence by protein chip array. J Obstet Gynaecol Res 38:89-96
Wen, Yan; Ho, Jason Yen-Ping; Polan, Mary Lake et al. (2011) Expression of apoptotic factors in vaginal tissues from women with urogenital prolapse. Neurourol Urodyn 30:1627-32
Yen-Ping Ho, Jason; Man, Weng Chi; Wen, Yan et al. (2010) Transforming growth interacting factor expression in leiomyoma compared with myometrium. Fertil Steril 94:1078-83
Man, Weng Chi; Ho, Jason Yen-Ping; Wen, Yan et al. (2009) Is lysyl oxidase-like protein-1, alpha-1 antitrypsin, and neutrophil elastase site specific in pelvic organ prolapse? Int Urogynecol J Pelvic Floor Dysfunct 20:1423-9
Chen, Bertha; Wen, Yan; Yu, Xiao Yun et al. (2009) Relaxin increases elastase activity and protease inhibitors in smooth muscle cells from the myometrium compared with cells from leiomyomas. Fertil Steril 91:1351-4
Wen, Y; Man, W C; Sokol, E R et al. (2008) Is alpha2-macroglobulin important in female stress urinary incontinence? Hum Reprod 23:387-93
Wen, Y; Zhao, Y Y; Li, S et al. (2007) Differences in mRNA and protein expression of small proteoglycans in vaginal wall tissue from women with and without stress urinary incontinence. Hum Reprod 22:1718-24
Chen, Bertha; Wen, Yan; Zhang, Zhaomei et al. (2006) Microarray analysis of differentially expressed genes in vaginal tissues from women with stress urinary incontinence compared with asymptomatic women. Hum Reprod 21:22-9
Chen, Bertha; Wen, Yan; Yu, Xiaoyun et al. (2005) Elastin metabolism in pelvic tissues: is it modulated by reproductive hormones? Am J Obstet Gynecol 192:1605-13
Chen, Bertha; Wen, Yan; Polan, Mary Lake (2004) Elastolytic activity in women with stress urinary incontinence and pelvic organ prolapse. Neurourol Urodyn 23:119-26

Showing the most recent 10 out of 14 publications