Autopsy pathology, Cardiac pathology

Lipids are important regulators of the activity of many proteins including those involved in cardiac, vascular, pulmonary, and neural regulation, yet little is known about the molecular mechanisms mediating these effects. My laboratory staff members are engaged in a program of basic research to elucidate the molecular mechanisms by which lipids act as specific ligands to regulate cellular responses, and to investigate in select areas of cardiovascular disease how aberrations of signaling pathways may play a vital role in the pathogenesis of human disease. We have used the family of phosphoinositide-specific phospholipase C isoforms as a model to study protein-lipid interactions. Upon stimulation by various hormones these membrane associated enzymes hydrolyze polyphosphoinositides to yield second messengers such diacylglycerol and inositol 1,4,5-trisphosphate. The determinants of enzyme function are complex and can be broken down into several primary components: substrate binding and catalysis, enzyme translocation, and regulation. During the past several years we have identified the structural motifs in the PLC delta 1 isoform that mediate each of the three primary functions. All three motifs require the binding of a specific lipid for function. The structural motif mediating translocation also modulates the rate catalysis, and is encoded by a unique domain termed the pleckstrin homology or PH domain. This newly discovered protein module of 100 amino acids exists in many molecules (including PLC d1) that participate in signal transduction. Our research is among the first to demonstrate a clear function in signal transduction for the PH domain, and serves a paradigm for the activation and regulation of many signaling molecules.