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

• 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
• 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

 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，在世界范围内发病率迅速增加。单核细胞衍生的巨噬细胞（MP）和血管平滑肌细胞（VSMC）参与早期脂肪条纹形成、中间斑块进展，重要的是，参与晚期斑块坏死核心扩张和纤维帽变薄，这决定了斑块破裂的可能性，斑块破裂是不稳定型心绞痛、心肌梗死或中风等临床事件的最常见近端原因。降低促炎活性、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细胞募集、死亡和尸体积累的循环，这些循环驱动坏死核心扩张和斑块不稳定。为了促进新的治疗策略，介导这些理想的活动的发展，该项目旨在了解分子机制控制MP和VSMC活动，有助于易损斑块的形成和破裂。这些研究的重点是一种称为同种异体移植炎性因子-1（Aif-1）的蛋白质，也称为离子化结合衔接子-1（Iba 1），其最初被表征为直接参与吞噬作用和肌动蛋白捆绑的细胞质MP蛋白。Aif-1缺乏经典的分泌信号，但最近的报道表明，Aif-1具有 作为细胞外可溶性因子的活性，包括促炎作用。我们假设 EC和ICAif-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ECAif-1而不影响ICAif-1可以限制炎性细胞因子的产生，同时保留使MP能够清除由炎症和细胞死亡引起的细胞碎片的吞噬活性。我们提出了三个目标，在其中，我们将比较IC和EC Aif-1如何差异影响MP和VSMC活动，测试MP和VSMC Aif-1在体内小鼠模型血管重塑和动脉粥样硬化的相对重要性，并确定是否抑制EC Aif-1而不限制IC Aif-1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对Aif-1功能的分子见解，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。