Office: SSB 7142 Phone: (778) 782-6801
Research Interests:Cholesterol is a necessary evil. Although it is a major cause of heart disease, cholesterol is nonetheless an indispensible part of our cells and their membranes. In my laboratory, we study the biological role of cholesterol and its impact on human health. An immediate goal of our research is to identify mechanisms of intracellular cholesterol transport conserved both in humans and baker's yeast, Saccharomyces cerevisiae. We are exploiting the power of yeast molecular genetics, cell biology, and genomics to identify and study genes required for sterol-lipid transport within yeast cells. In a complementary line of research, we are studying intercellular cholesterol transport in the worm Caenorhabditis elegans. We are developing genetic screens and using reverse genetics to analyze the molecular mechanisms governing cholesterol regulation and movement in C. elegans. By applying yeast and worm molecular genetics, we intend to unravel the complexities of cholesterol function to better understand human cholesterol-related disorders.
We are using yeast molecular genetics to determine the mechanism of human Niemann-Pick Type C disease, a fatal neurodegenerative disease that afflicts children and adolescents. The yeast genome encodes a gene similar to the defective human gene in Niemann-Pick Type C disease called NPC1. We are applying techniques such as yeast functional genomics and molecular genetics to uncover the normal function of the yeast NPC1-like gene. By analyzing the yeast gene, we are learning more about its human counterpart and the cause of Niemann-Pick Type C disease.
Our research also examines the Oxysterol-binding protein (OSBP) gene family, which are implicated in cholesterol/sterol-lipid transport in human and yeast cells. Mammalian OSBP binds with great affinity to oxygenated versions of cholesterol, oxysterols, and translocates between internal cellular membranes in response to oxysterol binding. The yeast OSBP family consists of seven genes, OSH1-OSH7. When we delete all these OSH genes from yeast, the cells die. However, in the absence of all the other OSH genes, just one OSH gene is enough to keep yeast cells alive. This demonstrates that all seven OSH genes can, by themselves, provide the function necessary for yeast survival. We have made yeast strains in which the OSH genes can be turned-on and -off. When the OSH genes are on the cells grow but when we turn off the OSH genes, the cells accumulate large amounts of ergosterol (the yeast equivalent of cholesterol) indicating a defect in intracellular ergosterol transport. In addition, we observe by electron microscopy that in these cells some organelles breakdown and there is a disruption in endocytosis. Our interest now is to determine what other genes and proteins regulate and interact with the Oshs, and to understand their cellular role. To help us in this pursuit, we are both applying genomic methods, such as high density DNA microarrays for gene expression studies, and designing new technologies involving yeast functional genomics.
Yeast synthesize their own sterols and normally do not import sterols from outside the cell. Worms do not have the ability to make their own sterols and must ingest them. Humans both make and ingest sterols. In a collaboration with the Hawkins laboratory, we are designing genetic screens to isolate worm mutants that have difficulties in internalizing sterols. In addition, we are screening candidate mutants representing homologous genes to those involved in human cholesterol transport. In this way, we are using yeast to identify conserved mechanisms of intracellular transport, and worms, to isolate genes and proteins required for intercellular transport. Both approaches are applicable to human cholesterol biology, and promise a better understanding of cholesterol-related disease.
Last updated 08/31/2001