Cystic fibrosis (CF)-related diabetes (CFRD) is present in upwards of 20% of adolescents and 40-50% of adults with CF and is associated with significant glycemic variability, poor glycemic control, and unpredictable hypoglycemia. CFRD is increasing in prevalence as new disease-modifying therapies have led to a significant increase in life expectancy in those with CF. While the etiology of CFRD is poorly understood, pancreatic islet cells, responsible for the production of insulin, somatostatin, glucagon, and other hormones, are subject to immune-mediated inflammation in CFRD. In CF, chronic inflammation and infection may lead to tissue damage, fibrosis, and overall impaired pancreatic function, culminating in destruction of the insulin producing beta cells resulting in diabetes and impaired counterregulatory responses. Even in type 1 diabetes, an autoimmune disease with the similar feature of beta cell destruction, changes in the beta cell-immune cell interface during disease pathogenesis remain largely unknown. Therefore, understanding the role and composition of the pancreas landscape in the context of CF may provide clues to the pathogenesis of CFRD and our global understanding of how beta cells and immune cells interact. We recently used CO-Detection by indEXing (CODEX) imaging to elucidate islet cell composition and surrounding immune infiltrate to understand the role of CF in CFRD/ pancreatic function. Our preliminary analysis demonstrated a landscape of infiltration in the context of CFRD that could provide insight into pathogenesis. In this project, we propose to build on these results using the Xenium Prime 5K Human Pan Tissue & Pathways Panel to evaluate gene expression at the single cell level in fresh frozen pancreas tissue sections from the same organ donors used for CODEX. We expect this powerful side-by-side analysis to provide unprecedented knowledge regarding the beta cell-immune cell interface and its altered landscape in CFRD disease development.
