AIF-1 Expression in VSMC Growth and Arteriopathy

描述（由申请人提供）：作为VSMC对损伤反应的一部分，VSMC迁移到血管的管腔中，在那里它们增殖并合成细胞因子，它们以自分泌的方式做出反应，维持管腔直径的损失。在HL63810的过程中，我们已经确定了异体移植物炎症因子-1 （AIF-1）的表达，一种新描述的细胞质钙结合蛋白，可预测临床移植血管病变的发展。损伤颈动脉中AIF-1的表达显著加剧了管腔直径的减少，并向外膜募集骨髓细胞。AIF-1的敲除可消除新生内膜增生。在人VSMC中表达AIF-1增加迁移、增殖，诱导G-CSF表达，激活Pad GTPase。AIF-1包含几个信号域，结合和聚合肌动蛋白，并激活信号转导蛋白。我们的数据支持我们的中心假设，即AIF-1是一种炎症反应性支架蛋白，在VSMC激活和新生内膜增生的发展中起关键作用。该应用程序的总体目标是：1-确定体内AIF-1表达与新生内膜增生之间的因果关系；2-表征VSMC中AIF-1活性的细胞途径和分子机制。为了验证这一假设，我们制定了三个目标；1- AIF-1表达加剧新生内膜增生，AIF-1表达降低可减少血管成管术损伤大鼠和AIF-1转基因小鼠的新生内膜增生；2- AIF-1直接激活Rac1信号通路导致G-CSF表达，AIF-1直接激活G-CSF表达，随后自分泌激活Rac信号通路，3- AIF-1通过激活gef激活Rac1。并通过激活转录因子诱导G-CSF表达。表征AIF-1功能将澄清我们对炎症介导的信号转导导致VSMC病理生物学和血管免疫细胞串扰的理解。

DESCRIPTION (provided by applicant): As part of the VSMC response to injury, VSMC migrate into the lumen of the vessel where they proliferate and synthesize cytokines which they respond to in an autocrine fashion, sustaining the loss of lumen diameter. In the course of HL63810, we have determined that expression of Allograft Inflammatory Factor-1 (AIF-1), a newly described cytoplasmic, calcium-binding protein, is predictive of development of clinical transplant vasculopathy. Expression of AIF-1 in injured carotid artery significantly exacerbates reduction of lumen diameter and recruits bone marrow cells to the adventitia. Knock-down of AIF-1 abrogates neointimal hyperplasia. Expression of AIF-1 in human VSMC increases migration, proliferation, induces expression of G-CSF, and activates the Pad GTPase. AIF-1 contains several signaling domains, binds to and polymerizes actin, and activates signal transduction proteins. Our data support our central hypothesis that AIF-1 is an inflammation-responsive scaffold protein that plays a key role in regulation of VSMC activation and development of neointimal hyperplasia. The overall goals of this application are to 1- determine a cause and effect relationship between AIF-1 expression and neointimal hyperplasia in vivo, and 2- characterize the cellular pathways and molecular mechanisms responsible for AIF-1 activity in VSMC. Three aims have been formulated to test the hypothesis that; 1- AIF-1 expression exacerbates neointimal hyperplasia, and that reduction of AIF-1 expression will reduce neointimal hyperplasia in angioplasty-injured rats and AIF-1 transgenic mice, 2- that AIF-1 directly activates Rac1 signaling pathways leading to G-CSF expression, and that AIF-1 directly activates G-CSF expression with a subsequent autocrine activation of the Rac signaling pathway, and 3- AIF-1 activates Rac1 by activation of GEFs, and induces G-CSF expression by activation of transcription factors. Characterization of AIF-1 function will clarify our understanding of inflammation-mediated signal transduction leading to VSMC pathobiology and vascular- immune cell cross talk.