Dissecting estrogen signaling in gut epithelial-nerve interactions

About This Grant

PROJECT SUMMARY Visceral pain from the gut shows a strong sex bias, with women three times more likely to develop IBS than men. In females, this sensitivity is tightly linked to ovarian hormone fluctuations, particularly estrogen. While preclinical studies implicate estrogen in modulating visceral pain, its underlying mechanisms remain unclear. My postdoctoral research shows that estrogen influences visceral sensitivity via paracrine signaling between two enteroendocrine cell (EEC) types in the intestinal epithelium. Building on this, my K99/R00 proposal will identify estrogen-responsive molecular changes in EECs and mucosal afferents (K99), and define how stress and estrogen signaling interact in the epithelium to drive visceral hypersensitivity and chronic pain (R00). In the Ingraham lab at UCSF, and through collaborations with the Julius, Brierley, and Bayrer labs, I helped uncover a critical role for enterochromaffin (EC) cells and mucosal nerves in sex-dependent visceral pain. These insights raised compelling questions about how estrogen impacts gut-nerve communication. I have since discovered a potent, estrogen-sensitive interaction between EC cells and another EEC subtype, L-cells, that amplifies visceral pain in females. This proposal is driven by three key discoveries: 1. estrogen receptor ERα is expressed in colonic L-cells and is necessary for heightened visceral sensitivity in females; 2. estrogen induces PYY release from L-cells, which acts as a nociceptive signal; and 3. PYY stimulates EC cells to release serotonin, which activates mucosal afferents and triggers visceral pain. These findings form the basis for the proposed aims investigating how estrogen signaling shapes gut-neural circuits that underlie chronic pain. In K99 Aim 1, I will use CUT&RUN epigenome sequencing, in vitro organoid assays, and in vivo functional assessments to determine how estrogen signaling in L-cells drives PYY release. In Aim 2, I will examine how epithelial estrogen signaling influences sensory afferent function through in vivo calcium imaging. During the R00 phase (Aim 3), I will leverage the techniques acquired during the K99 phase to investigate how hormonal and stress signals converge on the gut-nerve axis to amplify visceral pain, ultimately contributing to hypersensitivity and chronic pain. With primary mentorship from Dr. Holly Ingraham and co-mentorship from Dr. David Julius, I will continue to deepen my expertise in epithelial biology, endocrinology, and pain science while gaining advanced training in epigenomic and imaging techniques. My proposed research will uncover molecular and neural mechanisms underlying hormonal modulation of visceral hypersensitivity and identify novel targets for better pain management. Overall, my proposed research and training plans will support transition to an independent research career.