Junying Yuan, Ph.D.
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-------------------------------------------------------------------------------- Caspase-11 is an upstream caspase which we have shown previously required for activation of caspase-1 and pro-IL-1ß processing. While the expression of caspase-11 is undetectable in most tissues of healthy mice, it can be induced by a variety of pathological signals. Caspase-11-deficient mice showed a defect in processing pro-IL-1ß as well as reduced number of apoptotic cells and a defect in caspase-3 activation. We concluded that caspase-11 is an upstream caspase in mediating cytokine secretion as well as apoptosis under brain ischemia and systemic inflammation. Unfolded protein response in endoplasmic reticulum has been implicated in mediating neuronal cell death in Alzheimer's disease. We found that caspase-12 is localized in ER and a deficiency in caspase-12 renders cortical neurons specifically resistant to amyloid ß protein toxicity. Our work demonstrated a novel ER-specific apoptosis pathway. Chemical genetic approaches to dissect the mechanism of Bcl-2. Heterodimerization of pro- and anti-apoptotic members of the Bcl-2 family through their BH3 domains is critical for regulating cell survival. To further characterize the role of BH3 domain interaction and develop prototypic small molecule inhibitors of Bcl-2 family, we developed a high throughput screen for Bcl-2 inhibitors. We isolated two series of Bcl-2 inhibitors and demonstrated by in vivo and in vitro experiments that they induce apoptosis through inhibiting BH3 domain interaction. Similar chemical genetic approaches are being used in the laboratory to dissect other pathways involved in regulating physiological and pathological cell death.
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