Role of Metallothionein 1 E in the Protection of Cystic Fibrosis-Related Diabetes

PROJECT SUMMARY/ABSTRACT Cystic fibrosis (CF) is the fifth leading cause of death in the US. As a life-shortening genetic disease, CF is characterized by abnormalities in the pulmonary and digestive systems due to systemic inflammation, fibrosis, and tissue degradation. About half of adult CF patients experience cystic fibrosis related diabetes (CFRD). Unlike the common type I or type II diabetes, CFRD develops at the very early stages of life of people with CF and leads to greatly worsened lung disease. Although new therapeutics – such as the triple combination CFTR modulator therapy TRIKAFTA – are impacting lung function for many patients, these therapies do not appear to be solving the endocrine problems experienced by people with CF. More precise and effective methods of early detection of this disease are urgently needed for progression prevention and to drastically lower the death rate. This project, if successful, will transform the management of patients with CFRD into more effective treatment strategies. Our first goal is to understand the role of MT1E on β-cell functions and survival during the development of CFRD. Our second goal is to elucidate the impact of exocrine cells expressing mutant CFTR on endocrine islets. Our third goal is to resolve a single-cell (scRNA-seq) map of islets from healthy, CFRD, and TRIKAFTA-treated CF ferrets. Our central hypothesis is that redox imbalance and tissue remodeling contribute to CFRD progression by altering endocrine function through the metallothionein 1 E pathway. First, this project is expected to shed light on the molecular mechanism of Metallothionein 1E (MT1E) in regulating pancreatic damage in patients with CFRD, using pluripotent stem cell-derived human pancreatic exocrine and endocrine organoids. Second, by using cutting-edge collagen-based magnetic resonance imaging, this project will map the location and severity of fibrosis in the pancreas during the development of CFRD. Finally, performing high throughput single-cell RNA sequencing analysis of the pre-clinical model of CFRD, the CFTRG551D/-KI ferret, this project will identify essential biomarkers during the progression of CFRD. Ultimately, these studies broaden our understanding of the pathogenesis of CFRD and provide the basis for using Magnetic resonance imaging (MRI) as a potential diagnostic approach for disease early detection. The project also serves as an opportunity for the PI to shift directions in his research program, learning new techniques that will greatly enable his future career.