Grant: Project Grant

We have recently made an exciting discovery that impacts our understanding of how the plasma membrane (the membrane that encapsulates a cell) of animal cells interacts with molecules in the environment, including nutrients and drugs. For our studies, we use a nematode worm, called C. elegans, to better understand animal biology. For over 40 years, the study of this worm has lead to many discoveries that directly impact our understanding of human biology. In animals, the plasma membrane (PM) is composed of four different fat-like molecules called lipids. One of these lipids, called sphingomyelin (SM), is made by a SM biosynthetic pathway. Through our investigation of how chemicals interact with the worm, we discovered that the activity of this pathway is a key determinant of how molecules interact with the PM. When the SM pathway operates normally, large fat-loving molecules are able to associate with the PM, and smaller molecules are unable to pass through the PM. When the SM pathway is defective, the fat-loving molecules cannot associate with the PM, and smaller molecules can pass through the PM barrier. These observations impact our understanding of how drugs and fat-like nutrients get absorbed by cells. In AIMs 1 and 2 of this proposal, we describe our experiments to investigate this process in detail. One of the enzymes that we think operates in the SM biosynthetic pathway is called PGP-14. Evidence suggests that PGP-14 provides the SM pathway with a precursor, called phosphatidylcholine (PC), for SM synthesis. The human version of PGP-14 is called ABCB4, which provides PCs in the liver so that the body can absorb fats. When ABCB4 doesn't work, children develop an incurable liver disease called PFIC3 and require a liver transplant to survive. In AIM3 of this grant, we use PGP-14 worm mutants as a tool to find drugs that will make up for the lack of PGP-14/ABCB4 biochemical activity in the hopes of providing a cure for children suffering from PFIC3.