Allograft inflammatory factor-1 in atherosclerosis

同种异体移植物炎症因子-1在动脉粥样硬化中的作用

基本信息

批准号：
8913555
负责人：
Nicholas E Sibinga
金额：
$ 27.53万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2015-03-16 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913555
关键词：
Abbreviations Actins Affect Apolipoprotein E Arterial Fatty Streak Arterial Lines Arteries Atherosclerosis Binding Blood Vessels Blood coagulation Blood flow Bone Marrow Bundling Cause of Death Cell Cycle Cell Death Cell Surface Receptors Cell physiology Cells Cessation of life Characteristics Cholesterol Clinical Coagulation Process Cytoplasm Deposition Development Diet Event Fatty acid glycerol esters Goals Growth Human In Vitro Incidence Inflammation Inflammatory Interleukins Intervention Knock-out Left Mediating Molecular Mus Myocardial Infarction NF-kappa B Necrosis Organ Pathway interactions Phagocytosis Physiological Play Process Production Proteins Public Health Recombinants Relative (related person)Reporting Role Rupture Signal Transduction Site Small Interfering RNA Smooth Muscle Myocytes Societies Staging Stroke Testing Therapeutic Transgenic Mice Unstable angina Vascular remodeling Work allograft inflammatory factor-1 atherogenesis base cell type cytokine disability extracellular feeding in vivo insight macrophage migration monocyte mouse model novel therapeutics overexpression paracrine prevent public health relevance response to injury restoration theories therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis remains a major public health problem in Western-style societies, with rapidly increasing incidence worldwide. Monocyte-derived macrophages (MPs) and vascular smooth muscle cell (VSMCs) participate in early fatty streak formation, intermediate plaque progression, and importantly, in advanced plaque necrotic core expansion and fibrous cap thinning that determine the likelihood of plaque rupture, the most frequent proximal cause of clinical events such as unstable angina, myocardial infarction, or stroke. Interventions that decrease pro-inflammatory activities, prevent VSMC demise, and promote macrophage clearance function could break the cycle of cell recruitment, death, and corpse accumulation that drives necrotic core expansion and plaque instability. To promote the development of novel therapeutic strategies that mediate such desirable activities, this project seeks to understand molecular mechanisms controlling MP and VSMC activities that contribute to vulnerable plaque formation and rupture. The focus of these studies is a protein called allograft inflammatory factor-1 (Aif-1), also known as Ionized binding adapter-1 (Iba1), which was initially characterized as a cytoplasmic MP protein involved directly in phagocytosis and actin bundling. Aif-1 lacks a classical secretory signal, but recent reports suggest that Aif-1 has activities as a soluble factor outside the cell, including pro-inflammatory effects. We hypothesize that EC and IC Aif-1 mediate distinct cellular functions, and that the ability to manipulate these functions separately may have therapeutic value - selective blockade of EC Aif-1 without affecting IC Aif-1 could limit inflammatory cytokine production, while preserving the phagocytic activities that enable MPs to clear cellular debris that results from inflammation and cell death. We propose three aims, in which we will compare how IC and EC Aif-1 differentially affect MP and VSMC activities, test the relative importance of MP and VSMC Aif-1 in in vivo mouse models of vascular remodeling and atherogenesis, and determine whether inhibition of EC Aif-1 without limiting IC Aif-1 can reverse the processes that promote necrotic core expansion and plaque destabilization. We anticipate that these studies will provide molecular insight into Aif-1 function and test its viability as a potential therapeutic target in strategies to decrease plaque rupture.

描述（由申请人提供）：动脉粥样硬化仍然是西方社会的一个主要公共卫生问题，其发病率在世界范围内迅速增加，单核细胞源性巨噬细胞（MP）和血管平滑肌细胞（VSMC）参与早期脂肪纹形成、中间斑块。进展，重要的是，晚期斑块坏死核心扩张和纤维帽变薄决定斑块破裂的可能性，斑块破裂是不稳定心绞痛等临床事件最常见的近端原因，减少促炎活性、防止 VSMC 死亡和促进巨噬细胞清除功能的干预措施可以打破导致坏死核心扩张和斑块不稳定的细胞募集、死亡和尸体积累的循环。为了介导此类所需活性的新颖治疗策略，该项目旨在了解控制 MP 和 VSMC 活性的分子机制，这些活性有助于易损斑块形成和破裂，这些研究的重点是一种称为同种异体移植物炎症因子-1 的蛋白质。 (Aif-1)，也称为离子化结合接头-1 (Iba1)，最初被定性为直接参与吞噬作用和肌动蛋白捆绑的细胞质 MP 蛋白，但最近的报告表明 Aif-1 缺乏经典的分泌信号。 -1有作为细胞外可溶性因子的活性，包括促炎作用。 EC 和 IC Aif-1 介导不同的细胞功能，并且单独操纵这些功能的能力可能具有治疗价值 - 选择性阻断 EC Aif-1 而不影响 IC Aif-1 可以限制炎症细胞因子的产生，同时保留吞噬细胞活性我们提出了三个目标，其中我们将比较 IC 和 EC Aif-1 对 MP 和 VSMC 活性的差异影响，测试 MP 和 VSMC 的相对重要性。 Aif-1在体内血管重塑和动脉粥样硬化形成的小鼠模型中的作用，并确定在不限制IC Aif-1的情况下抑制EC Aif-1是否可以逆转促进坏死核心扩张和斑块不稳定的过程，我们预计这些研究将提供分子证据。深入了解 Aif-1 功能并测试其作为减少斑块破裂策略中潜在治疗靶点的可行性。