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.)

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD064824-03
Application #
8291898
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Meikle, Susan
Project Start
2010-08-17
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$316,479
Indirect Cost
$117,279
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Papke, Christina L; Yanagisawa, Hiromi (2014) Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies. Matrix Biol 37:142-9
Budatha, Madhusudhan; Silva, Simone; Montoya, Teodoro Ignacio et al. (2013) Dysregulation of protease and protease inhibitors in a mouse model of human pelvic organ prolapse. PLoS One 8:e56376
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Funato, Noriko; Nakamura, Masataka; Richardson, James A et al. (2012) Tbx1 regulates oral epithelial adhesion and palatal development. Hum Mol Genet 21:2524-37
Moller, Henrik Devitt; Ralfkjaer, Ulrik; Cremers, Natascha et al. (2011) Role of fibulin-5 in metastatic organ colonization. Mol Cancer Res 9:553-63

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