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（由适用提供）：动脉粥样硬化仍然是西方风格社会的主要公共卫生问题，全球发病率迅速增加。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，中间斑块的进展，重要的是，在先进的斑块坏死性核心膨胀和纤维帽稀薄的情况下，可以确定plaque priptials the My频繁的事件，例如，la频率的事件是临床上的一致性事件。梗塞或中风。减少促炎活性，防止VSMC灭亡并促进巨噬细胞清除功能的干预措施可能会破坏细胞募集，死亡和尸体积累的循环，从而驱动坏死核心的扩张和斑块不稳定。为了促进调解此类理想活动的新型治疗策略的发展，该项目旨在了解控制MP和VSMC活动的分子机制，从而有助于易受伤害的斑块形成和破裂。这些研究的重点是一种称为同种异体移植炎性因子-1（AIF-1）的蛋白质，也称为电离结合衔接子1（IBA1），最初以直接参与吞噬细胞增多症和肌动蛋白束的细胞质MP蛋白来表征。 AIF-1缺乏经典的秘密信号，但最近的报道表明AIF-1有活动是细胞外的固体因素，包括促炎作用。我们假设 EC和IC AIF-1培养基不同的细胞功能，并且分别操纵这些功能的能力可能具有治疗价值 - 不影响IC AIF-1的EC AIF-1的选择性阻断可以限制炎症性细胞因子的产生，同时可以保留吞噬活性，从而使MPS能够清除炎症和细胞死亡导致的细胞脱发。 We propose three aims, in which we will compare how IC and EC Aif-1 Differently 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.我们预计，这些研究将提供对AIF-1功能的分子见解，并将其生存能力作为减少斑块破裂的策略中潜在的治疗靶标。