ER-associated protein Reticulon in atherosclerosis

动脉粥样硬化中的 ER 相关蛋白 Reticulon

基本信息

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
项目类别：
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

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 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（由适用提供）：确定动脉粥样硬化的发病机理时巨噬细胞内质网应激（ER）尚不完全了解。该提案的核心目的是检查ER相关蛋白Nogo-B在动脉粥样硬化中的作用。我们已经表明，Nogo-B在内皮细胞（EC），血管平滑肌细胞（VSMC）和具有多种细胞特异性功能的单核细胞/巨噬细胞中高度丰富。 Nogo-B（Nogo - / - ）的遗传损失导致伪影损伤后夸张的新内膜形成。 Nogo-B的表达与动脉粥样硬化的严重程度负相关，表明Nogo-B的局部还原可能有助于形成斑块和/或不稳定。我们令人兴奋初步数据表明，与ApoE-/ - 小鼠相比，Nogo - / - 小鼠在APOE敲除背景（APOE - / - Nogo - / - ）上会产生更大，更先进的动脉粥样硬化病变，巨噬细胞凋亡增加，巨噬细胞凋亡增加。 ApoE - / - Nogo - / - 小鼠也发展出严重的冠状动脉狭窄，这种表型在当前的动脉粥样硬化小鼠模型中很少观察到。与野生型小鼠相比，Nogo - / - 巨噬细胞响应游离胆固醇的负荷而易于凋亡。我们还表明，Nogo-B可以分泌并从EC中分泌到体外和体内，并且外源性Nogo-B可以防止巨噬细胞凋亡。我们假设Nogo-B控制着巨噬细胞的功能，以调节动脉粥样硬化斑块的形成和坏死。在该提案中，我们将：（1）定义巨噬细胞Nogo-B在体内动脉粥样硬化斑块的进展和坏死中的作用，（2）询问细胞内在的NOGO-B调节ER应激的细胞诱导的NOGOPOPHOPS在体外的巨噬细胞和（3）的质量促成的NOOG-BOCOR-BINOG-BINOG-BINOG-BINOG-BINOG-BINOG-BINOG-BINOG-BORTOCH的作用，并促进了无效的作用。体内。这项研究的发现将推进Nogo领域，从而提供见解，以了解ER相关的网状蛋白如何调节血管稳态。