William J. Craigen, MD

Clinical Interests - Genetic Disorders and Metabolic Disorders.

Research Interests - Mitochondrial function: Mitochondria are now recognized to play a variety of important physiologic roles in various processes beyond ATP synthesis, including programmed cell death (apoptosis), retrograde signaling, cellular proliferation, and the regulation of intermediary metabolism. One area of interest in the lab is in understanding the role of the mitochondrial outer membrane permeability in the regulation of cellular energy economy, apoptosis and mammalian organ function. Voltage-dependent Anion Channels (VDAC1-3: also known as mitochondrial porins) are a family of mitochondrial outer membrane proteins that conduct small molecules across the outer membrane. VDACs also bind cytosolic kinases such as hexokinase isoforms, and may act to tether other multi-protein complexes to mitochondria. One isoform (VDAC2) functions in suppressing apoptosis by binding the multi-domain pro-apoptotic protein BAK, while other isoforms play roles in glucose metabolism, learning and memory, and fertility. Using model organisms we are interested in determining the specific functions of each isoform in biology and relating VDAC function to disease states. These studies involve biochemical, physiologic, and genetic experimentation.

Human metabolic disorders: Despite advances in identifying human metabolic diseases, pathophysiologic mechanisms are poorly understood and specific treatment strategies lacking. Others projects in the laboratory involve studies of metabolic pathways leading to human inherited disorders. Using mutant mice, our current studies are designed to understand the metabolic disturbances that are associated defects in phospholipid and fatty acid metabolism, purine and creatine synthesis, and mitochondrial respiratory chain activities. We are interested in defining cell type-specific functions for the enzymes of intermediary metabolism using knockout mice in conjunction with tissue-specific transgene expression.