Our laboratory focuses on molecular mechanisms of apoptosis, especially the role of the caspase family of cell death proteases in apoptosis and disease. One of our major interests is the regulation of caspases by heat shock proteins such as alphaB-crystallin. We have demonstrated that alphaB-crystallin is a novel cell death antagonist that inhibits apoptosis by disrupting the activation of caspase-3. In addition, we have shown that alphaB-crystallin is commonly expressed in a variety of cancers and confers resistance to a broad range of apoptotic stimuli, including chemotherapy drugs. We are currently examining the detailed mechanisms by which alphaB-crystallin inhibits caspase-3 activation, and we are exploring alphaB-crystallin as a potential therapeutic target in cancer. A second major interest of our group is the identification and characterization of the proteolytic targets of caspases. Using a novel expression cloning strategy, we have identified many new caspase substrates, including the DNA repair proteins RAD21 and MLH1 that are converted into pro-apoptotic molecules by caspase cleavage. Moreover, we have demonstrated that caspases link the two major neuropathologies in Alzheimer’s disease, amyloid and neurofibrillary tangles. Specifically, amyloid exposure of neurons activates caspases, which cleave the cytoskeletal protein tau and promote tau assembly into tangles. We are also investigating the relationship between caspase cleavage of tau and neuronal apoptosis. In this way, these studies are providing new insights into the mechanisms of apoptosis and its role in disease.