Research Projects

The goal of my research is to identify the regulatory proteins that control vesicle transport in the yeast Saccharomyces cerevisiae, in order to understand how underlying defects in protein and lipid trafficking contribute to human disease.

Vesicle transport is required to switch off signaling receptors that would otherwise promote unregulated cell growth and cancer. Identifying the factors that regulate the intracellular sorting of lipids such as cholesterol is a first step in the development of new treatments for diseases such as atherosclerosis. Because vesicle transport processes are highly conserved, they can be studied in a very simple organism, and the findings applied directly to the study of human cells. Yeast genetics is therefore a powerful tool for the discovery of fundamental cellular mechanisms relevant to human health.

Vesicle traffic is regulated by factors that select cargo for incorporation into a forming vesicle and direct its docking and fusion with the appropriate target membrane. The machinery that controls transport between two intracellular compartments—the endosome and the trans-Golgi network—is of particular interest because these compartments act as relay stations, directing a large number of different sorting events. We have used a genetic approach in the yeast model system to identify four components of a conserved protein complex (GARP: Golgi-associated retrograde protein complex) that directs the targeting of transport vesicles with the trans-Golgi network. We are currently using genetic, cell biological and biochemical techniques to analyze the interactions that link this vesicle targeting complex to other components of the membrane fusion machinery.

Recent advances in genome-wide phenotypic screening in yeast, combined with powerful bioinformatics analyses, hold great promise for the rapid and comprehensive identification of novel multi-subunit complexes. Functional genomics is expected to uncover most of the genes required for the trafficking of proteins and lipids through Golgi and endosomal compartments. In genome-wide screens, we have identified a set of genes likely to act together at a common regulatory step in protein sorting. We are now using biochemical/cell biological assays to characterize interacting proteins and analyze their role in protein and lipid trafficking in detail. Tackling a problem at many different levels—from genome-wide discovery studies in yeast, to the biochemical and cell biological characterization of specific protein complexes, to the investigation of homologous proteins in mammalian cells—allows an in-depth analysis of protein function and ensures that discoveries made in a simple model organism are efficiently translated to the study of medically relevant processes in mammalian cells.

Please visit my lab website to learn more about my research.