Spinal cord injury (SCI) affects >15 million individuals globally, with 500,000 new cases/year. SCI not only causes paralysis but also disrupts the neural circuitry and signaling in the gastrointestinal (GI) tract. Gut dysfunction is an overlooked consequence of SCI, presenting as impaired colonic motility and altered gut microbiota. This project will investigate the relationship between SCI and colonic function, identifying the molecular and cellular players involved.
Enteric glial cells (EGCs) play a vital role maintaining the function of the enteric nervous system (ENS). EGCs are involved in regulating GI motility, secretion, and barrier function. EGCs also play a crucial role in mediating GI immune responses. However, the exact mechanisms by which SCI affects EGCs and the related consequences for gut functions remain uncharacterized. We will examine the central hypothesis that EGC reactivity after SCI promotes gut dysfunction and that preventing EGC activation after SCI will reduce enteric gliosis, and reduce the ENS changes. Aim1 will evaluate the impact of increasing EGC reactivity on SCI-induced gut dysfunction. The impact on physiological functions will be assessed ex vivo through epithelial ion transport or transepithelial resistance (TER) (Cox; years 1-2) and in vivo (year 2) by measuring changes in motility, microbiome/metabolite populations and systemic inflammation (Geoffroy, year 2). Histological assessments will monitor changes in gliosis, gut inflammation and fibrosis (Geoffroy, years 2-3), as well as barrier integrity and ENS functions (Cox, year 2). Aim2 is to identify molecular targets in the EGC and determine strategies that could reduce SCI-induced EGC activation and alleviate SCI-induced gut dysfunctions (years 2-3). Aim3 is to develop a new in vitro screening system to identify clinically-approved drugs and natural gut metabolites that reduce TER (year 3). Identified drugs will then be tested in vivo to determine their efficacy at preventing gut dysbiosis and other dysfunctions after SCI (years 3-4). The student will gain a wide range of skills including spinal cord microsurgery, electrophysiology, and microbiome/metabolomic analysis. They will utilise new technologies to develop a viral strategy to activate EGC and to label ENS and will also develop a new tissue clearing protocol for 3D imaging and AI-based quantification of the colonic epithelial morphology.