Project 466758

Our body relies on peptide hormones to control a variety of biological processes involved in growth metabolism. Peptide hormones are first produced as larger proteins (prohormones), which are further processed into their mature form by a class of enzymes known as prohormone convertases (PCs). In our gut, we have special cells (known as enteroendocrine cells) that produce a type of peptide hormone known as glucagon-like peptide (GLP)-1, which is necessary for the control of blood glucose levels, GLP-2, which is important for intestinal growth. GLP-1 GLP-2 are both derived from their larger precursor, proglucagon.Emerging evidence over the past 3 decades has shown that infants born with defects in the PCSK1 gene (which gives rise to the prohormone convertase PC1/3) have multiple hormone-related abnormalities, with a notable one being severe malabsorptive diarrhea. In this condition, infants often fail to thrive as they are unable to absorb nutrients within the small intestine. This can ultimately threaten the survival of affected infants if adequate nutrition is not given through alternative means.Our lab hypothesizes that PC1/3 is a crucial enzyme involved in the production of GLP-1 and GLP-2 from proglucagon, both of which may have implications in both diabetes severe malabsorptive diarrhea. For my graduate project, I hope to determine whether defective GLP-1 and GLP-2 production leads to diabetes impaired intestinal absorption, respectively. This will be achieved by studying a strain of mice that lack the PCSK1 gene within the enteroendocrine cells of the small intestine. This study will provide new insights into the genetic causes of intestinal disorders within humans, leading the way for the development of novel treatments for affected individuals.