ER-associated protein Reticulon in atherosclerosis

动脉粥样硬化中的 ER 相关蛋白 Reticulon

• 批准号: 8860819
• 负责人: Jun Yu
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-05 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860819
• 关键词: Accounting; Apolipoprotein E; Apoptosis; Apoptotic; Area; Arterial Fatty Streak; Arterial Injury; Arteries; Atherosclerosis; BCL2 gene; Biological; Blood Vessels; Bone Marrow Transplantation; Calcium; Cardiac; Cardiovascular Diseases; Cause of Death; Cell model; Cells; Cessation of life; Cholesterol; Chronic Obstructive Airway Disease; Coronary Stenosis; Data; Development; Disease; Endoplasmic Reticulum; Equilibrium; Event; Family; Genetic; Goals; Golgi Apparatus; Grant; Heart failure; Homeostasis; Human; In Vitro; Knock-out; Lead; Length; Lesion by Stage; Link; Mediating; Mediator of activation protein; Membrane Proteins; Mitochondria; Modeling; Molecular Models; Morphology; Mus; Myelogenous; Myocardial dysfunction; Necrosis; Nogo protein; Pathogenesis; Patients; Phenotype; Play; Protein Family; Protein Isoforms; Proteins; RTN1 gene; Regulation; Reporting; Research; Research Support; Role; Rupture; Serum; Severities; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Smooth Muscle Myocytes; Societies; Staging; Therapeutic; Tissues; Vascular Endothelial Cell; Vesicle; Wild Type Mouse; Work; angiogenesis; atherogenesis; endoplasmic reticulum stress; gain of function; in vivo; insight; loss of function; macrophage; molecular modeling; monocyte; mortality; mouse model; neointima formation; novel; plaque lesion; prevent; protein transport; public health relevance; relating to nervous system; response; trafficking

 DESCRIPTION (provided by applicant): Macrophage endoplasmic reticulum (ER) stress in regulating the pathogenesis of atherosclerosis is not fully understood. The central goal of this proposal is to examine the role of ER-associated protein Nogo-B in atherosclerosis. We have shown that Nogo- B is highly abundant in endothelial cells (EC), vascular smooth muscle cells (VSMC) and monocytes/macrophages with diverse and cell-specific function. The genetic loss of Nogo-B (Nogo-/-) results in exaggerated neointima formation after arterial injury. The expression of Nogo-B negatively correlates with the severity of atherosclerosis, suggests that the local reduction of Nogo-B might contribute to plaque formation and/or instability. Our exciting preliminary data demonstrate that Nogo-/- mice on an ApoE knockout background (ApoE-/-Nogo-/-) develop larger and more advanced atherosclerotic lesions with increased macrophage apoptosis compared to ApoE-/- mice. The ApoE-/-Nogo-/- mice also developed severe coronary stenosis, a phenotype that is rarely observed in current mouse models of atherosclerosis. Nogo-/- macrophages are much more prone to apoptosis in response to free cholesterol loading compared to those of wild-type mice. We also show that Nogo-B can be secreted and transferred from ECs to macrophages in vitro and in vivo, and that exogenous Nogo-B can prevent macrophage apoptosis. We hypothesize that Nogo-B governs macrophage functions to regulate atherosclerotic plaque formation and necrosis. In this proposal, we will: (1) define the role of macrophage Nogo-B in atherosclerotic plaque progression and necrosis in vivo, (2) interrogate the mechanisms by which cell intrinsic Nogo-B regulates ER stress induced macrophage apoptosis in vitro, and (3) examine the non-cell- autonomous effects of Nogo-B in macrophage function in vitro and atherogenesis in vivo. The findings of this study will advance the Nogo field, providing insights in understanding how ER-associated reticulon proteins regulate vascular homeostasis.

 描述（由申请人提供）：巨噬细胞内质网（ER）应激在调节动脉粥样硬化发病机制中的作用尚未完全了解。本研究的主要目的是研究ER相关蛋白Nogo-B在动脉粥样硬化中的作用。我们已经发现，Nogo- B在内皮细胞（EC）、血管平滑肌细胞（VSMC）和单核细胞/巨噬细胞中高度丰富，具有多种细胞特异性功能。Nogo-/-基因缺失导致动脉损伤后过度的新生内膜形成。Nogo-B的表达与动脉粥样硬化的严重程度呈负相关，提示Nogo-B的局部减少可能有助于斑块的形成和/或不稳定。整理的丰厚 初步数据表明，与ApoE-/-小鼠相比，ApoE敲除背景的Nogo-/-小鼠（ApoE-/-Nogo-/-）发展出更大和更晚期的动脉粥样硬化损伤，巨噬细胞凋亡增加。ApoE-/-Nogo-/-小鼠也发生了严重的冠状动脉狭窄，这是一种在目前的动脉粥样硬化小鼠模型中很少观察到的表型。与野生型小鼠相比，Nogo-/-巨噬细胞更容易响应游离胆固醇负荷而凋亡。我们还表明，Nogo-B可以分泌和转移从EC巨噬细胞在体外和体内，外源性Nogo-B可以防止巨噬细胞凋亡。我们推测Nogo-B通过控制巨噬细胞的功能来调节动脉粥样硬化斑块的形成和坏死。在本提案中，我们将：（1）确定巨噬细胞Nogo-B在体内动脉粥样硬化斑块进展和坏死中的作用，（2）探究细胞内在Nogo-B调节ER应激诱导的巨噬细胞凋亡的体外机制，和（3）检查Nogo-B在体外巨噬细胞功能和体内动脉粥样硬化形成中的非细胞自主作用。这项研究的结果将推进Nogo领域，为理解ER相关的reticulon蛋白如何调节血管稳态提供见解。