Mechanisms linking CFTR to dysregulated barrier function, insulin receptor function, and glucose transport in the CF lung

Emory University, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY In Cystic Fibrosis (CF), one of the most common lethal genetic diseases in the U.S., loss of CFTR function leads to the well-known triad of infection, inflammation, and obstruction, resulting in progressive loss of lung function. As CF patients develop CF-related diabetes (CFRD), the most common CF comorbidity, lung function decline is accelerated. Despite the high frequency and substantial clinical significance of CFRD, little is known about how the development of systemic hyperglycemia worsens airway function in CF. Published work from the McCarty-Koval labs detailed the discovery of fundamental defects in the handling of glucose in the CF airway, including impacts on both the function of tight junction proteins in limiting flux of glucose into the airway and the function of transporters to remove airway glucose from the airway surface liquid (ASL), two arms that together generate an “airway glucose barrier.” Furthermore, our results show that non-CF airway epithelial cells responded to insulin by enhancing barrier function, while cells expressing mutant CFTR (CF cells) responded to insulin by weakening barrier function. New preliminary data suggest that while insulin-mediated signaling in non-CF cells occurs through the “metabolic” pathway, supportive of tight junction integrity and glucose uptake, insulin-mediated signaling in CF cells occurs through the “mitogenic” pathway, which is detrimental to barrier integrity. Our general hypothesis is that expression of mutant CFTR alters expression and localization of tight junction proteins to impact barrier function while also altering glucose transport from the ASL, and that insulin signaling pathways serve as a hub to coordinate the activities of both barrier and glucose transport functions; we also hypothesize that acute ingestion of glucose in CF patients leads to increased glucose abundance and enhanced oxidative stress in the airway. The goal of this proposal is to determine the underlying mechanisms for dysregulation of glucose barrier function in the CFRD airway. Aim 1 will identify mechanisms that link expression of mutant CFTR to altered insulin receptor function and impacts of hyperglycemia and airway redox stress. Aim 2 will identify mechanisms linking expression of mutant CFTR to altered glucose barrier function and impacts of hyperglycemia and redox stress. Aim 3 will determine the kinetics of change in glucose abundance and glucose-induced redox imbalance in the CFRD airway in response to oral glucose challenge in human subjects in a small clinical study. This highly mechanistic proposal builds upon strong preliminary data and takes advantage of an outstanding investigative team comprised of experts in cell biology, gene expression, diabetes, and redox. The potential impacts of this research include the identification of mechanism(s) linking diabetes to enhanced pulmonary decline in CFRD and identification of pathways that could be therapeutically targeted to control airway glucose and its effect on pulmonary disease progression.