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Charles H. Hood Foundation | Kaelyn Sumigray, Ph.D. – January 2022
By identifying innovative pediatric advancements and providing funding in the critical phases of development, we are able to expedite high-impact breakthroughs that improve the health and lives of millions.
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Kaelyn Sumigray, Ph.D.

Assistant Professor of Genetics

Yale School of Medicine

Identifying the Cell of Origin in Intestinal Cystic Fibrosis Disease


Key Words: Intestine, Cystic fibrosis, Stem cell, Cell fate

Cystic fibrosis (CF) is a devastating inherited disorder that causes severe damage to the lungs, digestive system, and other organs, resulting in dramatically reduced life expectancy. CF is caused by mutations in the CFTR gene, whose protein function is to balance the flow of salts and water across the surface of tissues. In CF, the mutated CFTR protein fails to transport sufficient chloride ions out of the cell, causing decreased fluid secretion and creating a dehydrated and acidic environment within the affected tissues. In the intestine, this dehydrated environment results in mucus buildup, causing intestinal obstruction and bacterial overgrowth. In newborns, this manifests as meconium ileus and most often requires surgical intervention. Throughout life, CF patients suffer from intestinal obstruction and bacterial overgrowth, leaving them at risk for Crohn’s disease and colorectal cancer. Unfortunately, there are no medical treatments that can reverse the disease process in the gut because little is known about how CFTR is regulated, and the relevant cell types have not been identified. Our recent findings have implicated a rare subpopulation of intestinal cells that express more CFTR protein than neighboring cells, unexpectedly revealing a specialized cell type on the luminal surface of the gut. Our proposal is based on the hypothesis that these cells, known as CFTR High Expressers (CHEs), are the primary sites of CFTR activity and are therefore responsible for the mechanism of CF intestinal disease. To understand how CHEs contribute to CF, the crucial first step is to determine how these cells are produced and to determine what function they have in normal healthy intestine. In our first aim, we seek to identify the master regulators of CHEs, the networks of transcription factors that specify production of the CHE cell type and that instruct the functions that these cells carry out. In our second aim, we will evaluate if and how CHEs regulate fluid secretion and pH within the intestinal lumen and determine how these key functions are affected in CF. If successful, our findings will provide a rigorous mechanistic explanation of CF intestinal disease, paving the way for early intervention treatments.