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: 9201339
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201339
• 关键词: 7-ketocholesterol; Acrosome Reaction; Address; Applications Grants; Arteries; Atherosclerosis; Autophagocytosis; Autophagolysosome; Bacteria; 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; Heart; Hydrolysis; Impairment; In Vitro; Inflammation; Injury; Lead; Lipids; Lysosomes; Mammalian Cell; Mediating; Medical Genetics; Membrane; Microtubules; Molecular; Motor; Movement; Mus; Muscle Cells; Mutation; Myocardial Infarction; Names; Niemann-Pick Diseases; Organelles; Pathogenesis; Pathologic; 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; acid sphingomyelinase; atherogenesis; emerging adult; hypercholesterolemia; in vivo; insight; new therapeutic target; novel therapeutics; oocyte maturation; public health relevance; 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(申请人提供)：溶酶体运输涉及许多细胞活动，如吞噬作用以保护哺乳动物细胞免受外来入侵，如细菌，自噬以保持这些细胞存活或健壮，以及与受体循环、钙释放和膜修复有关的细胞信号。到目前为止，人们对这种溶酶体运输和相关的自噬通量是如何在血管系统中进行调节的知之甚少。近年来的研究表明，神经酰胺是溶酶体酸性鞘磷脂酶(ASM)对神经鞘蛋白的一种水解产物，对冠状动脉平滑肌细胞(CASMCs)的溶酶体功能和冠状动脉功能具有重要的调控作用。临床上，ASM的遗传缺陷导致神经鞘蛋白的溶酶体积聚和一种称为尼曼-皮克病的溶酶体储存障碍。这些尼曼-皮克病患者在成年早期就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ASM-神经酰胺介导的溶酶体功能调节异常有关。在这项拨款提案中，我们的假设是ASM-神经酰胺信号通路在CASMC的溶酶体运输和自噬通量中起着关键的紧张性调节作用，这种溶酶体调节的不足可能是一个重要的动脉粥样硬化形成机制。我们将首先讨论溶酶体ASM及其在CASMCs中的产物神经酰胺是否有助于控制促动脉粥样硬化刺激下的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(目标1)。然后，我们将利用ASM-/-小鼠及其野生型胎鼠来确定ASM缺陷是否由于溶酶体转运调节失调和自噬小泡滞留而导致冠状动脉壁动脉粥样硬化性损伤(目标2)。最后，我们将使用AS-/-小鼠及其野生型窝仔(AIM)来研究溶酶体运输的失调和由此导致的自噬通量的失败如何在体外和体内导致CASMCs和冠状动脉壁的动脉粥样硬化变化。这项拨款申请将首次涉及通过ASM/神经酰胺途径积极调节CASMCs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。这一研究结果将为溶酶体功能的紧张性调节以及与血管疾病可能的病理相关性提供新的见解，这可能有助于确定治疗和预防动脉粥样硬化的新靶点。