Regulation of Lysosome function in Cellular Physiology and Pathology
My lab focuses on the mechanisms of programmed cell death, which plays a central role in causing heart failure in response to ischemic injury and pressure overload hypertrophy. We have found that autophagy is impaired in cardiac ischemia-reperfusion injury secondary to impaired autophagosome clearance, due to defects in late stages of autophagy. Forcibly expressing transcription factor EB (TFEB), a master regulator of lysosomal pathways, induce lysosomal biogenesis and rescues cardiac myocytes from cell death in this setting. We posit that a similar limitation in lysosome numbers or function contributes to lysosomal dysfunction in other disease including Alzheimer’s Disease, where accumulating evidence points to insufficient lysosomal proteolysis in multiple cell types as contributing to amyloid plaque deposition and progression. We are now collaborating to test these hypotheses in vivo with Dr Jin-Moo Lee whose program has demonstrated expertise in modeling Alzheimer’s Disease. We have developed the tools that permit us to perform gain-of-function and loss-of-function of TFEB and evaluate its effects on cell biology, including APP proteolysis in neurons; and amyloid uptake and processing in astrocytes and microglia.