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Role of RTN-4 in Atherosclerosis

RTN-4 在动脉粥样硬化中的作用

基本信息

批准号：
8732749
负责人：
Jun Yu
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732749
关键词：
Acute Apolipoprotein E Apoptosis Apoptotic Area Arterial Fatty Streak Arterial Injury Arteries Atherosclerosis BCL2 gene Biological Blood Vessels Blood flow Bone Marrow Transplantation Calcium Cardiac Cardiovascular Diseases Cause of Death Cells Cessation of life Cholesterol Chronic Obstructive Airway Disease Coronary Stenosis Data Development Disease Endoplasmic Reticulum Endothelial Cells Equilibrium Event Family Gene Delivery Genes Genetic Goals Golgi Apparatus Grant Heart failure Homeostasis Human Hypoxia In Vitro Inflammatory Response Integral Membrane Protein Ischemia Knock-out Lasers Lead Length Lesion by Stage Link Lung Mammals Membrane Proteins Microscopy Mitochondria Modeling Molecular Morphology Mus Myelogenous Necrosis Oligodendroglia Pathogenesis Patients Phenotype Protein Family Protein Isoforms Proteins RTN1 gene Recovery Regulation Research Research Support Role Rupture Serum Severities Signal Pathway Signal Transduction Signal Transduction Pathway Smooth Muscle Myocytes Staging Therapeutic Tissues Up-Regulation Vascular Endothelial Cell Vesicle Wild Type Mouse Work angiogenesis atherogenesis axon growth congenic endoplasmic reticulum stress gain of function in vivo inhibitor/antagonist insight loss of function macrophage monocyte mortality mouse model neointima formation novel plaque lesion prevent protein transport public health relevance repaired response trafficking

项目摘要

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 RTN-4B (aka, Nogo-B), an integral membrane protein mainly localized to the ER, in macrophage ER stress and 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 and impaired blood flow recovery post-ischemia. Nogo-B regulates acute inflammatory response in EC and suppresses hypoxia-induced pulmonary VSMC apoptosis. In humans, 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 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) elucidate 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 functions. The findings of this study will advance the Nogo field, providing insights in understanding how Nogo 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不完全清楚。这项建议的中心目标是研究RTN-4B(又名Nogo-B)在巨噬细胞内质网应激和动脉粥样硬化中的作用。我们已经证明，Nogo-B在内皮细胞(EC)、血管平滑肌细胞(VSMC)和单核/巨噬细胞中含量丰富，具有多种细胞特异性功能。Nogo-B(Nogo-/-)基因缺失导致动脉损伤后新生内膜的过度形成和缺血后血流恢复受阻。Nogo-B调节EC的急性炎症反应，抑制缺氧诱导的肺VSMC凋亡。在人类中，Nogo-B的表达与动脉粥样硬化的严重程度呈负相关，提示局部Nogo-B的减少可能有助于斑块的形成和/或不稳定。我们令人兴奋的初步数据表明，与ApoE-/-小鼠相比，ApoE基因敲除背景的Nogo-/-小鼠(ApoE-/-Nogo-/-)会发展出更大、更严重的动脉粥样硬化病变，巨噬细胞凋亡增加。ApoE-/-Nogo-/-小鼠还出现了严重的冠状动脉狭窄，这是目前动脉粥样硬化小鼠模型中很少观察到的一种表型。与野生型小鼠相比，Nogo-/-巨噬细胞在自由胆固醇负荷下更容易发生凋亡。我们还表明，Nogo-B可以从内皮细胞分泌并转移到巨噬细胞，外源性Nogo-B可以防止巨噬细胞的凋亡。我们推测，Nogo-B调控巨噬细胞调节动脉粥样硬化斑块形成和坏死的功能。在这个方案中，我们将：(1)明确巨噬细胞Nogo-B在体内动脉粥样硬化斑块进展和坏死中的作用；(2)阐明细胞内源性Nogo-B在体外调节ER应激诱导巨噬细胞凋亡的机制；(3)研究Nogo-B在巨噬细胞功能中的非细胞自主作用。这项研究的发现将推动Nogo领域的发展，为理解Nogo如何调节血管内稳态提供见解。