Allograft inflammatory factor-1 in atherosclerosis

 描述(申请人提供)：动脉粥样硬化在西式社会中仍然是一个主要的公共卫生问题，在全球范围内发病率迅速上升。单核细胞来源的巨噬细胞(MPS)和血管平滑肌细胞(VSMCs)参与早期脂肪条纹的形成、斑块的中级进展，重要的是参与晚期斑块坏死性核心扩张和纤维帽变薄，这决定了斑块破裂的可能性，而斑块破裂是不稳定心绞痛、心肌梗死或中风等临床事件最常见的近端原因。减少促炎活性、防止VSMC死亡、促进巨噬细胞清除功能的干预措施可以打破细胞募集、死亡和身体堆积的循环，从而推动坏死性核心扩张和斑块不稳定。为了促进新的治疗策略的发展，以中介这种理想的活动，该项目试图了解控制MP和VSMC活动的分子机制，这有助于易损斑块的形成和破裂。这些研究的重点是一种名为同种异体移植物炎症因子-1(AIF-1)的蛋白质，也被称为离子结合适配器-1(IBA1)，最初的特征是直接参与吞噬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 活性作为细胞外的一种可溶性因子，包括促炎作用。我们假设 EC和IC AIF-1介导不同的细胞功能，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可以限制炎性细胞因子的产生，同时保留使MPS能够清除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，其中我们将比较IC和EC AIF-1如何不同地影响MP和VSMC的活性，测试MP和VSMC AIF-1在体内小鼠血管重塑和动脉粥样硬化模型中的相对重要性，以及确定抑制EC AIF-1而不限制IC AIF-1是否可以逆转促进坏死核扩张和斑块失稳的过程。我们预计这些研究将提供对AIF-1功能的分子洞察力，并测试其作为减少斑块破裂策略的潜在治疗靶点的可行性。

 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.