Lysosome trafficking has been implicated in a number of cellular activities such as phagocytosis to protect mammalian cells from foreign invaders like bacteria, autophagy to keep these cells surviving or robust, and cellular signaling related to receptor recycling, Ca2+ release and membrane repairing. So far little is known how such lysosome trafficking and associated autophagic flux are regulated in the vasculature. Recent studies have demonstrated that ceramide, a hydrolysis product of sphingomyelin by lysosomal acid sphingomyelinase (ASM), contributes to the control of lysosome functions in coronary arterial smooth muscle cells (CASMCs) and coronary arterial function. Clinically, genetic defects of ASM lead to the lysosomal accumulation of sphingomyelin and a lysosomal storage disorder named Niemann-Pick disease. These Niemann-Pick disease patients are susceptible to the development of atherosclerosis in early adulthood, suggesting that the pathogenesis of atherosclerosis may be associated with the abnormality of ASM-ceramide-mediated regulation of lysosome function. In this grant proposal, our hypothesis is that ASM-ceramide signaling pathway plays a critical tonic regulatory role in lysosome trafficking and autophagic flux in CASMCs and the deficiency of this lysosome regulation may be an important atherogenic mechanism. We will first address whether lysosomal ASM and its product ceramide in CASMCs contribute to the control of lysosome trafficking and associated autophagic flux upon proatherogenic stimulations and to explore the molecular mechanisms by which ASM- ceramide signaling pathway controls lysosome trafficking and fusion (Aim 1). Then, we will determine whether the defect of ASM leads to atherosclerotic injury in coronary arterial wall due to dysregulation of lysosome trafficking and retention of autophagic vesicles using Asm-/- mice and their wild type littermates (Aim 2). Lastly, we will examine how dysregulation of lysosome trafficking and consequent failure of autophagic flux induce atherogenic changes in CASMCs in vitro and in coronary arterial wall in vivo using As--/- mice and their wild type littermates (Aim ). This grant application will for the first time address the molecular mechanisms that actively regulate lysosome trafficking and function via ASM/ceramide pathway in CASMCs and the physiological and pathological relevance to vascular regulation and atherosclerosis. The findings from this proposal will provide new insights into the tonic regulation of lysosome function and the possible pathological relevance to vascular diseases, which may help identify new therapeutic targets for treatment and prevention of atherosclerosis.
This grant proposal will test the role of a signaling pathway in the regulation of normal artery function in mouse heart and then further elucidate the possible contribution of such signaling deficiency to artery hardening. This signaling pathway relates to a lipid substance, namely, ceramide. We will demonstrate that this lipid importantly controls the movement of lysosome, a tiny body within arterial muscle cells. If such control of lysosome movement is impaired, the cell self-defending or surviving mechanism is disturbed, which promotes atherosclerosis (artery hardening) and consequent heart attack. It is anticipated that the findings from this grant proposal will provide experimental evidence that may direct toward the development of possible novel therapeutic strategies for artery hardening or heart attack.
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