Pelvic floor disorders affect up to one-third of adult women. One of the most prevalent pelvic floor disorders is pelvic organ prolapse, a condition in which the pelvic organs (bladder, vagina, cervix and uterus) herniate through the vaginal opening. Up to 11% of women have surgery for pelvic organ prolapse or urinary incontinence in their lifetime and more than 225,000 inpatient surgical procedures for pelvic organ prolapse are performed per year in the United States at an estimated annual direct medical cost of over one billion dollars. Although multiple mechanisms have been hypothesized to contribute to the development of pelvic organ prolapse, none fully explain the origin and natural history of this process. Epidemiologic studies indicate that vaginal birth and aging are the two major risk factors for developing pelvic organ prolapse. During the last funding period, we used mouse models of pelvic organ prolapse and tissues from women with and without prolapse to investigate the overall hypothesis of our research program, namely that vaginal wall support is maintained by a delicate balance between the synthesis/assembly and degradation of elastic fibers in the vaginal wall. In this application, we propose to build on this solid foundation to (i understand the relative importance of elastic fiber structural integrity and protease activation in the pathogenesis of pelvic organ prolapse, (ii) investigate the contribution of a novel elastin microfibrillar protein, LTBP4, and TGF? signaling in the pathogenesis of pelvic organ prolapse, and (iii) utilize injectable nanoparticle hydrogels with or without estrogen to prevent or ameliorate development of vaginal prolapse after injury.

Public Health Relevance

Women with pelvic organ prolapse suffer from urinary incontinence or retention, chronic pelvic pressure, fecal incontinence or obstruction, sexual dysfunction, social embarrassment and isolation. Experiments are proposed to understand how loss of matrix support of the pelvic organs leads to prolapse, and if connective tissues of the pelvic floor can be rescued and restored with matrix-specific therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (UGPP)
Program Officer
Murthy, Mahadev
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Obstetrics & Gynecology
Schools of Medicine
United States
Zip Code
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; Roshanravan, Shayzreen; Zheng, Qian et al. (2011) Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. J Clin Invest 121:2048-59
Huang, Jianbin; Davis, Elaine C; Chapman, Shelby L et al. (2010) Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ Res 106:583-92
Word, R Ann; Pathi, Sujatha; Schaffer, Joseph I (2009) Pathophysiology of pelvic organ prolapse. Obstet Gynecol Clin North Am 36:521-39
Wieslander, Cecilia K; Rahn, David D; McIntire, Donald D et al. (2009) Quantification of pelvic organ prolapse in mice: vaginal protease activity precedes increased MOPQ scores in fibulin 5 knockout mice. Biol Reprod 80:407-14
Rahn, David D; Acevedo, Jesus F; Roshanravan, Shayzreen et al. (2009) Failure of pelvic organ support in mice deficient in fibulin-3. Am J Pathol 174:206-15
Wieslander, Cecilia K; Marinis, Spyridon I; Drewes, Peter G et al. (2008) Regulation of elastolytic proteases in the mouse vagina during pregnancy, parturition, and puerperium. Biol Reprod 78:521-8
Rahn, D D; Acevedo, J F; Word, R A (2008) Effect of vaginal distention on elastic fiber synthesis and matrix degradation in the vaginal wall: potential role in the pathogenesis of pelvic organ prolapse. Am J Physiol Regul Integr Comp Physiol 295:R1351-8
Rahn, David D; Ruff, Matthew D; Brown, Spencer A et al. (2008) Biomechanical properties of the vaginal wall: effect of pregnancy, elastic fiber deficiency, and pelvic organ prolapse. Am J Obstet Gynecol 198:590.e1-6
Starcher, Barry; d'Azzo, Alessandra; Keller, Patrick W et al. (2008) Neuraminidase-1 is required for the normal assembly of elastic fibers. Am J Physiol Lung Cell Mol Physiol 295:L637-47