Medical Student Research Fellowship for Summer 2011
Mentor: Joseph L. Goldstein, M.D.
Department: Molecular Genetics
Room number: L5.238
Mail Code: 9046
Phone number: 214 648 2141
Project title: How NPC1 Transfers Cholesterol Out of Lysosomes
Human subjects IRB approved project number (where applicable): 062005-053
Animal subjects IRB approved project number (where applicable): 2009-310
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Basic Research
Brief Description of Project: Niemann-Pick Type C Disease (NPC) disease is an autosomal recessive lipid storage disease characterized by an error in trafficking of low-density lipoprotein (LDL)-derived cholesterol that is associated with lysosomal accumulation of excess cholesterol in cells. It is caused by a mutation in either one of two genes, NPC1 gene that encodes a 1278-amino acid protein with 13 putative membrane-spanning helices separated by a variety of loops, or NPC2 gene that encodes a 131-amino acid protein. NPC2 is a soluble glycosylated protein located in the lumen of the late endosomes/lysosomes and can be secreted into the medium of cultured cells. Cells lacking either NPC1 or NPC2 proteins accumulate LDL-derived cholesterol in lysosomes and fail to deliver LDL cholesterol to the plasma membrane and the endoplasmic reticulum (ER) where it performs structural and regulatory roles, respectively. Studies in our lab led us to advance a “hydrophobic handoff” model to explain the egress of LDL-derived cholesterol from lysosomes; Cholesterol is first bound by soluble NPC2 protein, which then hands off the cholesterol molecule to the N-terminal domain of membrane-bound NPC1. The next step, i.e., the process by which the cholesterol molecule is transported out of the lysosomal compartment, is unknown. We are currently using somatic cell genetics as a tool to identify the protein(s) that interact(s) with NPC1 and help export cholesterol out of lysosomes.
Previous Research Activities or Publications with Medical Students:
Ian McCoy- 2010
Mike McPhaul 1977-78