Calcium and Cell Death
The inositol 1,4,5-trisphosphate receptor (IP3R) is a ligand-gated ion channel which releases calcium from ER stores. IP3R plays a critical role in apoptotic calcium signaling. Our current efforts are focused on the molecular mechanisms leading to calcium release from IP3R in response to the death receptor ligand Fas. We have identified that PLC-gamma1 activation and subsequent calcium release from IP3R are required for Fas-mediated cell death. We are currently evaluating the role of Src kinases in PLC-gamma1 activation and calcium release. These studies are directed towards three major clinically relevant modalities of Fas signaling:
1) Fas and T lymphocyte apoptosis.
2) The “Fas-counterattack” hypothesis of tumor immune privilege.
3) Fas-mediated hepatocyte cell death, with a focus on Fas and liver injury caused by severe burn injury.
In addition to death receptor signaling, we are also investigating the evolutionary conservation of apoptotic signaling pathways which lead to calcium release. Finally, we are developing small molecule inhibitors of apoptotic calcium release from IP3R for the treatment of various disease states caused by deranged calcium signaling.
Alzheimer's Disease
Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with aging. Much of what we know about AD has been elucidated by the study of rare familial cases of AD which are associated with the production of toxic fragments of amyloid precursor protein (APP). Unlike familial cases of AD, the underlying causes of late-onset AD are poorly understood. Polymorphisms in the gene encoding the protein ubiquilin-1 may be a risk factor for late onset AD, and is one of the primary interests of the laboratory. We have three main areas of investigation aimed at understanding the pathogenesis of AD:
1) The effects of ubiquilin-1 on APP maturation, processing, and toxicity.
2) The "gene-dosage effect" of APP-mediated neurotoxicity.
3) The effects of familial mutations in APP on intracellular calcium homeostasis.
The ultimate goal of our investigations into the pathogenesis of AD is to better understand the molecular mechanisms mediating neurotoxicity in both familial and late-onset AD, and determine whether common mechanisms are shared by these devastating diseases.