# Targeting Novel Fibrogenic Signaling Pathways to Prevent Injury and Age-Related External Anal Sphincter Muscle Dysfunction > **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2024 · — ## Abstract Women Veterans are the fastest-growing population and pelvic floor disorders such as anal/fecal incontinence (FI) are highly prevalent in women. Fecal incontinence (accidental leakage of stools; FI) that occurs in a significant population of women (>7%), is attributed to childbirth-related injury to the external anal sphincter (EAS) and pelvic floor muscles, by a variety of mechanisms, i.e., stretch, ischemia, spontaneous avulsions and surgical incision (episiotomy). Many FI patients develop symptoms after about 5 decades of life and the risk increases with advancing age, the reasons for which are not clear. In addition, these patients show anatomical disruptions and impairment of EAS muscle function. Our animal (rabbit) studies confirm these findings and further demonstrate abnormal healing with increased fibrosis and disorganized fiber orientation in the regenerating muscle after experimental EAS myotomy. Similar charges were also seen in old animals. Our mechanistic studies show upregulation of fibrosis network involving Wnt-β catenin/ STAT3 proteins and a novel central hub for multi- receptor driven profibrogenic signaling, GIV/Girdin in the injured as well as old animals. We hypothesize that impaired muscle regeneration/fibrosis after EAS injury as well as increased muscle atrophy observed during advanced aging is mediated by common molecular pathways involving Wnt-Frizzled, β-Catenin/TCF/LEF, STAT- 3 and GIV/Girdin signaling proteins. A clear understanding of these molecular mechanisms involved in sphincter fibrosis/atrophy would enable the identification of a novel target for the development of innovative strategies to prevent/ treat this disorder. The specific aims of our studies are to determine: 1. Mechanisms of injury-related sphincter muscle dysfunction; 2. Mechanisms of age-related sphincter muscle dysfunction, and 3. Mechanisms of the cumulative impact of age on injury-related sphincter muscle function. We will use a rabbit model and several novel approaches, 1; longitudinal measurement of in-vivo length tension function of the EAS muscle in animals, 2; use of Wnt antagonists (sFRP2), small molecule inhibitors (STAT3) and gene silencing (Girdin siRNA) approach to modulate fibrogenic signaling networks with an ultimate goal of improving sphincter function in our studies. Mechanistic insights gained from these studies will not only examine the topic from the molecular level to the level of whole animals but also unravel novel targets for further development of treatment strategies to prevent muscle fibrosis both in the setting of post-injury and aging-related incontinence. Thus, our proposal is both conceptually novel (studies a novel fibrogenic signaling network), and innovative (uses novel approaches and interventions to study sphincter and improve sphincter function), paving the way for new treatment strategies Successful conclusion of this study has a high potential for clinical translation (development of anti-fibrotic interventi... ## Key facts - **NIH application ID:** 10801178 - **Project number:** 1I01BX006370-01 - **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM - **Principal Investigator:** RAVINDER K. MITTAL - **Activity code:** I01 (R01, R21, SBIR, etc.) - **Funding institute:** VA - **Fiscal year:** 2024 - **Award amount:** — - **Award type:** 1 - **Project period:** 2024-04-01 → 2028-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10801178 ## Citation > US National Institutes of Health, RePORTER application 10801178, Targeting Novel Fibrogenic Signaling Pathways to Prevent Injury and Age-Related External Anal Sphincter Muscle Dysfunction (1I01BX006370-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801178. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*