Assistant Professor Jefferson Knight, Ph.D., of the CU Denver Department of Chemistry was recently awarded a $228,000 grant from the National Institutes of Health to study molecules that interact with the cellular machinery that releases insulin into the bloodstream.
The process by which secretory vesicles attach to the outer membrane of a cell and fuse into a single membrane to facilitate this release is extremely important, as underscored by the awarding of the 2013 Nobel Prize in Medicine to three scientists who discovered and have begun to characterize the pathway: Randy Schekman, James Rothman, and Thomas Südhof. However, the mechanisms by which this pathway occurs are still not fully understood.
Several proteins interact reversibly with lipid molecules in the membranes in a way that catalyzes membrane fusion, thus overcoming otherwise prohibitive energy barriers. Although there is a substantial understanding of how some of these proteins work, the particular proteins active in insulin secretion have been less well studied. In particular, little is known about their role in disease states such as the progressive deterioration of insulin secretion that accompanies type 2 diabetes.
The award to Professor Knight will allow him and his coworkers to investigate how these proteins involved in insulin secretion interact with lipids to catalyze membrane fusion under both normal and disease-like conditions. Knight and his students will probe key differences that exist at the physical-chemical level between the proteins involved in insulin secretion and their counterparts in the better-characterized pathway of neurotransmitter release. The study will also measure how these protein-membrane interactions change in the presence of certain classes of molecules that are known to be more prevalent under diabetic conditions.
The results will lead to a better understanding of how such proteins contribute to insulin secretion in both healthy and diabetic states, with the long-term goal of uncovering new options for diabetes diagnosis and/or treatment. More broadly, Knight’s study will shed light on whether changes in protein-membrane interactions contribute to cellular defects that underlie many diseases.