Our proposal herein will focus on novel pharmacological strategies for the rehabilitation of "age-related anal incontinence" in the female Veteran population, the fastest growing segment of VA healthcare users. Age- related anal incontinence is a major medical condition in female population (>7%) which is under reported. The exact mechanism of this disorder is unclear. The most common cause of anal incontinence is childbirth related injury to external anal sphincter (EAS) muscle by a variety of mechanisms, i.e., stretch, ischemia, spontaneous avulsions and surgical incision (episiotomy). Age-related degenerative changes to anal sphincter muscles further impact sphincter functions. Many patients develop symptoms after the 5th decade of their life and this risk increases with advancing age. A clear understanding of the molecular mechanisms of anal incontinence after EAS muscle injury would enable the development of innovative strategies to treat this disorder. Our preliminary studies in animal model as well as in patients with anal incontinence suggest age-related impairment of EAS muscle functions (length-tension property). This muscle dysfunction is associated with increased fibrosis and disorganized fiber orientation in the regenerating muscle in the animal model. This impairment is likely to be aggravated by the age-related increase in the muscle fibrosis. Our studies demonstrate an increase in Wnt (?-catenin) signaling in the aging animals as well as young animals following EAS injury. In addition, injection of secreted related frizzled protein 2 (Sfrp2) an extracellular Wnt antagonist, improves the EAS muscle function following injury. Our hypothesis is that, increased Wnt signaling is a central driving mechanism for impaired muscle regeneration following anal sphincter injury as well as increased sphincter degenerative changes observed during advanced aging. Targeting Wnt signaling pathways could attenuate sphincter fibrosis and improve muscle function.
Our specific aims are: 1) To determine the role of Wnt/?-catenin signaling pathways in the regeneration of new muscle fibers, formation of fibrosis/ and EAS muscle function following surgical myotomy. 2) To evaluate the effect of aging on the EAS muscle function and determine the role of Wnt signaling pathways in the age related degenerative changes on the EAS muscle function. W e anticipate that the principles learned from these studies will enable the identification of novel therapeutic strategies to prevent age-related sphincter degeneration and also improve continence in the aging female Veteran population. In summation, the proposed pre-clinical study fulfills the objectives described in the SPiRE award as it has high potential for clinical translation (potential use of Wnt antagonists) to maximize functional recovery (anal continence function) in the aging Veteran population.

Public Health Relevance

The overall objective of this proposal is to improve the quality of life of the female Veteran patient population. The expansion of women in the military is reshaping the Veteran population, with women now constituting the fastest growing segment of eligible VA health care users. In recognition of the health care needs of women, the VA Office of Research &Development sponsored the first national VA Women's Health Research Agenda-setting conference to map research priorities to the needs of women Veterans in 2004. A major focus of this proposal is to evaluate the molecular mechanisms of age-related degenerative changes to anal sphincter function in an animal model. This is especially relevant to female Veterans (a growing population), as these degenerative changes will result in fecal incontinence. A long-term goal of this project is to develop novel molecular or pharmacological strategies to prevent age-related anal incontinence in the female Veteran population.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (I21)
Project #
1I21RX001408-01
Application #
8633331
Study Section
Special Emphasis Panel (RRDS)
Project Start
2013-10-01
Project End
2015-09-30
Budget Start
2013-10-01
Budget End
2015-09-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161