Lysosome Trafficking Dysregulation of Arterial Myocytes in Atherogenesis

动脉粥样硬化中动脉肌细胞的溶酶体运输失调

• 批准号: 9002899
• 负责人: PinLan Li
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002899
• 关键词: 7-ketocholesterol; Acrosome Reaction; Address; Applications Grants; Arteries; Atherosclerosis; Autophagocytosis; Autophagolysosome; Bacteria; Binding; Blood Vessels; Cells; Ceramide Signaling Pathway; Ceramides; Coronary; Coronary artery; Defect; Development; Disease; Dynein ATPase; Endocytosis; Enzymes; Exocytosis; Extracellular Matrix; Failure; Fertilization; Foam Cells; Functional disorder; Health; Heart; Hydrolysis; In Vitro; Inflammation; Injury; Lead; Lipids; Lysosomes; Mammalian Cell; Mediating; Membrane; Microtubules; Molecular; Motor; Movement; Mus; Muscle Cells; Mutation; Myocardial Infarction; Names; Niemann-Pick Diseases; Organelles; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Physiological; Play; Predisposition; Prevention; Production; Proteins; Recycling; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Sphingomyelins; Testing; Time; Vascular Diseases; Vesicle; Work; acid sphingomyelinase; atherogenesis; emerging adult; hypercholesterolemia; in vivo; insight; new therapeutic target; novel therapeutics; oocyte maturation; receptor; receptor recycling; repaired; trafficking; wasting

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：溶酶体运输与许多细胞活动有关，例如保护哺乳动物细胞免受外来入侵者（如细菌）的吞噬，保持这些细胞存活或强健的自噬，以及与受体回收，Ca2+释放和膜修复相关的细胞信号。到目前为止，人们对溶酶体运输和相关的自噬通量在脉管系统中是如何调节的知之甚少。近年来的研究表明，神经酰胺是溶酶体酸性鞘磷脂酶（ASM）水解鞘磷脂的产物，对冠状动脉平滑肌细胞（CASMCs）溶酶体功能和冠状动脉功能的控制有重要作用。临床上，ASM的遗传缺陷导致鞘磷脂的溶酶体积聚和溶酶体储存障碍，称为尼曼-匹克病。这些Niemann-Pick病患者在成年早期易发生动脉粥样硬化，提示动脉粥样硬化的发病机制可能与ams -神经酰胺介导的溶酶体功能调节异常有关。在本课题中，我们的假设是asm -神经酰胺信号通路在CASMCs溶酶体运输和自噬通量中起着关键的强直调节作用，溶酶体调节的缺失可能是一个重要的动脉粥样硬化机制。我们将首先探讨CASMCs中溶酶体ASM及其产物神经酰胺是否有助于控制溶酶体运输和相关的自噬通量，并探索ASM-神经酰胺信号通路控制溶酶体运输和融合的分子机制（Aim 1）。然后，我们将利用ASM -/-小鼠及其野生型幼崽确定ASM缺陷是否会由于溶酶体运输和自噬囊泡保留的失调而导致冠状动脉壁的动脉粥样硬化损伤（目的2）。最后，我们将利用As- /-小鼠及其野生型幼崽研究溶酶体运输失调和自噬通量的失败如何在体外和体内诱导CASMCs和冠状动脉壁的粥样硬化变化（Aim）。这项资助申请将首次解决CASMCs中通过ASM/神经酰胺途径积极调节溶酶体运输和功能的分子机制，以及与血管调节和动脉粥样硬化的生理和病理相关性。本研究结果将对溶酶体功能的强直调节及其与血管疾病的病理相关性提供新的见解，有助于发现治疗和预防动脉粥样硬化的新靶点。