CHIRP Program Leadership

Profile

Our laboratory focuses attention on the molecular basis of various secretory processes whose dysfunction results in human disease. Neurotransmitter and neurohormone release occur from nerve terminals, endocrine, and exocrine cells by a fusion mechanism sensitive to ionic calcium, GTP, protein kinase C, and other kinases. Two disease-related applications of these interests have been pursued: Synexin (annexin VII, ANX7) is a Ca2+ channel protein and newly identified member of the GTPase Superfamily which uniquely fuses membranes, and is regulated by Ca2+, GTP and various protein kinases. It is also a newly identified component of the "fusion machine" which is believed to mediate docking and fusion during exocytotic secretion. Defects in these processes have been implicated in the pathologies of hypertension and diabetes, among others. These exciting results have prompted Dr. Pollard to investigate how the protein works in vivo using methods of site directed mutagenesis, prokaryotic and eukaryotic mutant protein expression, adenovirus transduction, and transgenic and knockout technologies.

We have also applied our insights from synexin studies to the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which is important for exocrine secretory processes. This protein, which is defective in the most common genetic disease, cystic fibrosis (CF), has nucleotide binding domains which are highly homologous with the annexin gene family. Like annexins, these domains interact specifically with the membrane, and mutations known to cause CF disrupt these interactions. Molecular analysis of the structure of these domains have led to our development of compounds which are currently being tested clinically for treatment of cystic fibrosis. In addition to conventional molecular methods employed for this study, our other approaches include fluorescence spectroscopy, confocal microscopy, lipid biochemistry, and organic synthesis.