Research Interests
In my laboratory, we focus primarily on basic mechanisms of apoptosis, oftentimes referred to as programmed cell death or cell suicide. Apoptosis is critical for normal development and works in concert with mitosis to regulate cell number in most, if not all adult tissues and organs. Consequently, diseases associated with the inhibition of apoptosis, include various cancers and autoimmune diseases, whereas those associated with increased rates of apoptosis, include AIDS, neurodegenerative disorders (Alzheimer's Disease and Parkinson's Disease), myelodysplastic syndromes and ischemic injury (stroke and myocardial infarction). Numerous toxicants, including chemotherapeutic drugs, industrial chemicals and environmental pollutants, also induce apoptosis and, in most cases, do so by triggering the activation of cysteinyl aspartate-specific proteases, or caspases. So-called 'initiator' caspases are activated first through association with specific adapter proteins and in turn activate 'effector' caspases that cleave cellular proteins and dismantle the cell. Thus, caspases are activated through unique signal transduction pathways, and our goal is to better understand in molecular detail how these caspases are activated and how their activity can be modulated. We are currently interested in a multimeric, caspase-activating complex known as the Apaf-1 apoptosome. This large complex, formed in response to mitochondrial stress, binds to caspase-9 and forms a holoenzyme that subsequently recruits and activates caspase-3. In addition, we are investigating the mechanisms by which inhibitor-of-apoptosis (IAP) proteins, such as XIAP, and their antagonists, such as Smac/DIABLO, prevent or potentiate apoptosis, in some cases by associating with the Apaf-1 apoptosome and controlling the activity of associated caspases. In our studies, we utilize a number of molecular biology and biochemistry techniques, including RT-PCR, cDNA cloning, site-directed mutagenesis, recombinant protein expression and purification, mammalian cell transfection, immunoprecipitations, western blotting, flow cytometry and confocal microscopy.
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July 6, 2005 Faculty Directory College of Pharmacy at UT Austin Comments to: pharmacy@www.utexas.edu |
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