Impact of Peripheral Circadian Misalignment on Resiliency of Intestinal Barrier Function to Alcohol

项目摘要

Project Abstract Only 20-30% of heavy alcoholics develop alcohol-induced intestinal hyperpermeability and alcoholic liver disease (ALD). Thus, emphasizing other cofactors that play a critical role is necessary to better understand mechanisms behind pathogenesis. Recent years have seen an increased prevalence of circadian rhythm disruption that contributes to human disease pathogenesis such as colonic hyperpermeability. However, the role of peripheral circadian misalignment in barrier homeostasis of t he gastrointestinal tract (GIT) is incompletely understood. Our focus is on the peripheral circadian clock in relation to alcohol consumption. Peripheral circadian disruption can occur by eating close to the body’s biological rest period. This ‘wrong-time eating’ (WTE) can cause changes in the intestinal microbiota and their metabolites, which may mediate intestinal gut leakiness to alcohol. Thus, we will test the overall hypothesis that peripheral circadian disruption will decrease resiliency of the intestinal barrier function to alcohol, mediated through microbial metabolites . Aim 1: Establish that peripheral circadian disruption through WTE decreases resiliency of the colon to alcohol. We will disrupt peripheral circadian rhythms in PERIOD2 luciferase (PER2::Luc) reporter BL/6 mouse model and assess the effect of alcohol consumption on intestinal permeability and intestinal barrier function Aim 2: Demonstrate that bacterial metabolites impact peripheral circadian rhythms and mediate decreased resiliency of colonic barrier function. We will demonstrate that bacterial metabolites can affect circadian rhythms as well as mediate changes in intestinal barrier function through colonic PER2::LUC organoids. In this proposed research, I will expand knowledge regarding the impact of peripheral circadian misalignment on intestinal resiliency to alcohol. Additionally, I will investigate the effect of bacterial metabolites from peripherally circadian disrupted PER2::LUC mice. The proposed work will elucidate how wrong -time eating makes the gut more susceptible to injury by alcohol by mechanisms related to microbial dysbiosis and bacterial products. Successful completion of this research would greatly increase our understanding of a key co-factor in alcohol induced barrier disfunction. Ultimately, the establishment of colonic peripheral circadian misalignment in ALD and identifying the microbial metabolites associated with this phenotype will lead to the development of microbial and circadian related interventions and identify therapeutic targets to mitigate alcohol-induced damage. This proposal will enhance the trainee’s ability to conceptualize, develop, execute, and evaluate meaningful research questions with increasing independence and will help her develop into a productive, leading independent research scientist. The research project and ca reer development will be guided by an outstanding team of sponsors and the dissertation committee who are exceptionally well -suited to provide this guidance such as mastering state-of-the-art methods/techniques, mentorship, and the development of collaborative networks to ensure success of the trainee in the short-term and long-term.