AIF-1 Expression In VSMC Growth And Arteriopathy

描述（申请人摘要）：动脉粥样硬化引起的血管再狭窄 创伤是限制实体经济成功的最关键因素之一 器官移植和冠状动脉介入手术。一个受欢迎 有一种假说认为，马槟榔碱诱导的血管平滑肌细胞的活化和增殖可能与其对血管平滑肌细胞增殖的抑制作用有关。 中膜，在内膜增生中达到顶峰，是最关键的细胞 心脏移植物血管病（CAV）和球囊形成事件 血管成形术诱导的再狭窄。鉴定和功能表征 参与VSMC激活的基因产物是一种有前途的方法， 确定防治增殖性动脉病的目标， 血管增生性疾病。我们的假设是同种异体移植的炎症 因子-I（AIF-1）促进血管增殖性疾病的发展， 其对炎症细胞因子的反应能力以及参与 导致VSMC增殖的生长刺激途径。我们最近 显示调节人VSMC中的AIF- 1水平会影响VSMC的生长， 这些细胞。该项目的第一个目标将确定 AIF-I通过流动和细胞增殖的组合在人VSMC中的生长促进作用 细胞计数分析和研究细胞的表达和周转 周期相关蛋白。我们还将确定介导这些的区域， 通过AIF- 1蛋白的位点特异性修饰的作用。我们已经确定 AIF- 1与几种细胞质蛋白，包括一种新的 描述了称为LCBK 5的生长因子激活的脂质激酶。的第二个目的 该提案将确定AIF- 1-LCBK 5的功能重要性 相互作用和表征其他AIF-1相互作用肽，我们有 鉴定AIF- 1转录物的表达在促分裂原刺激的细胞中被诱导 外周血淋巴细胞（PBL）及其在子宫内膜异位症中的表达 来自移植心脏的活组织检查与ISHLT排斥评分相关。一 这项提案的最终目的是将AIF-1转录水平与人类的免疫缺陷相关联， 来自心脏移植受者的肌内膜活检和PBL， 通过几种临床和成像确定的动脉病的发展 指数。预计这些研究的完成将涉及 表达这种新的蛋白质作为抗再狭窄治疗的靶点， 移植物再狭窄替代标志物。

DESCRIPTION (Applicant's abstract): Vascular restenosis induced by arterial trauma is one of the most critical factors which limits the success o solid organ transplantation and coronary interventional procedures. A popular hypothesis is that the cytokine-induced activation and proliferation of VSMC in the media, culminating in intimal hyperplasia, is the most critical cellular event in formation of both cardiac allograft vasculopathy (CAV) and balloon angioplastyinduced restenosis. Identification and functional characterization gene products involved in VSMC activation is a promising approach for the identification of targets to combat proliferative arteriopathy observed in vascular proliferative disorders. Our hypothesis is that allograft inflammatory factor-I (AIF-1) promotes development of vascular proliferative disease based on its ability to respond to inflammatory cytokines and participate in the growth stimulatory pathways leading to proliferation of VSMC. We have recently shown that modulation of AIF- 1 levels in human VSMC impacts the growth of these cells. The first aim of this project will determine the mechanism of AIF-l growth promoting effects in human VSMC through a combination of flow cytometric analysis and investigation of expression and turnover of cell cycle-associated proteins. We will also identify regions that mediate these effects by site-specific modification of the AIF- 1 protein. We have determined that AIF- 1 partners with several cytoplasmic proteins, including a newly described growth factor-activated lipid kinase termed LCBK5. The second aim of this proposal will determine the functional significance of the AIF- 1-LCBK5 interaction and characterize the other AIF-1-interacting peptides we have identified. Expression of AIF- 1 transcript is induced in mitogen-stimulated peripheral blood lymphocytes (PBL), and its expression in endomyocardial biopsies from transplanted hearts correlates with ISHLT rejection scores. A final aim of this proposal will correlate AIF-1 transcript levels in endomyocardial biopsies and PBL from heart transplant recipients with development of arteriopathy as determined by several clinical and imaging indices. It is anticipated that completion of these studies will implicate expression of this novel protein as a target of anti-restenotic therapy and a surrogate marker of transplant restenosis.