PROJECT SUMMARY Irritable bowel syndrome (IBS) is a common and debilitating disorder with marked sex differences in clinical presentation and treatment outcomes that are poorly understood. The long-term goal of my research program is to identify the cellular and molecular mechanisms that underlie sex differences in IBS and other digestive disorders in order to develop more targeted and effective therapies for patients. Sex hormones, such as the androgens testosterone and 5α-dihydrotestosterone, naturally vary between men and women and could explain sex differences in IBS. Previous studies have suggested that androgen levels correlate with IBS symptoms, such as abdominal pain and altered stool frequency. Androgens are traditionally considered male reproductive hormones and it remains largely unknown what role they play in intestinal homeostasis. Determining the normal functions of androgen signaling in the gut is crucial for understanding why men and women are differentially affected by IBS and developing better treatments. This proposal builds on our preliminary data, which show that a large subset of neurons in the intrinsic nerve circuits of the colon expresses the androgen receptor, and that disrupting androgen levels in male mice dramatically slows intestinal motility. The objective of this application is to determine how androgen signaling in these neurons of the enteric nervous system (ENS) alters colonic motility. For Aim 1, we will use androgen receptor knockout mice to determine to what extent androgen signaling in enteric neurons regulates colonic motility. For Aim 2, we will determine how loss of gonadal androgens alters the function of enteric neurons in neurogenic motor patterns in the colon. The overarching rationale for this work is that determining the role of androgen signaling in the ENS will shed light on how hormonal deficits alter digestive health. The studies proposed are essential next steps to translating the correlative observations made in clinical studies of IBS into a pathophysiological understanding of how deficits in circulating androgens might cause GI dysmotility. Findings from this work will not only advance the fundamental understanding of GI motility, but also reveal the therapeutic potential of targeting androgen signaling pathways as a new, more effective and personalized approach to the treatment of IBS.