Allograft inflammatory factor-1 in atherosclerosis

点击翻译按钮获取中文摘要

 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.