AIF-1 Expression In VSMC Growth And Arteriopathy

描述(申请人摘要)：动脉引起的血管再狭窄 创伤是限制固态手术成功的最关键因素之一。 器官移植和冠状动脉介入手术。一位受欢迎的 假说是细胞因子诱导的VSMC激活和增殖 中膜是最关键的细胞，最终导致内膜增生。 心脏移植物血管病(CAV)和球囊形成事件 血管成形性再狭窄。鉴定和功能表征 参与VSMC激活的基因产物是一种很有前途的方法 确定目标以对抗增生性动脉病 血管增生性疾病。我们的假设是同种异体移植物发炎 I因子(AIF-1)促进血管增生性疾病的发生发展 关于它对炎性细胞因子的反应和参与 促进VSMC增殖的生长刺激途径。我们最近做了 研究表明，人VSMC中AIF-1水平的调节影响血管内皮细胞的生长 这些细胞。这个项目的第一个目标将决定 血管内皮细胞生长因子-L对血管内皮细胞的促生长作用 细胞表达和周转的细胞学分析及研究 循环相关蛋白。我们还将确定调解这些问题的地区 对AIF-1蛋白进行定点修饰的效果。我们已经决定 AIF-1与几种细胞质蛋白配对，包括一种新的 描述了名为LCBK5的生长因子激活的脂蛋白激酶。第二个目标是 该提案将决定AIF-1-LCBK5的功能意义 相互作用并鉴定我们已有的其他AIF-1相互作用肽 已确认身份。丝裂原刺激诱导AIF-1转录本的表达 外周血淋巴细胞及其在心内膜心肌中的表达 移植心脏的活组织检查与ISHLT排斥反应评分相关。一个 这项提案的最终目标是将AIF-1转录水平与 心脏移植受者的心内膜心肌活检和外周血淋巴细胞 几种临床和影像所确定的动脉病的发展 指数。预计这些研究的完成将牵涉到 该新蛋白的表达可作为抗再狭窄治疗的靶点 移植再狭窄的替代标记物。

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.