Role of Chemokine & T-Cell Receptors in HIV Pathogenesis

趋化因子的作用

• 批准号: 7121406
• 负责人: Ramesh K. Ganju
• 金额: $ 42.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121406
• 关键词: HIV envelope protein gp120; HIV infections; T cell receptor; T lymphocyte; apoptosis; biological signal transduction; calcium flux; chemokine receptor; clinical research; cysteine endopeptidases; enzyme activity; gene expression; heat shock proteins; host organism interaction; human subject; pathologic process; patient oriented research; protein degradation; protein protein interaction; protein structure function; protein tyrosine phosphatase; transcription factor

DESCRIPTION (provided by applicant): The HIV-envelope protein gp120 plays a critical role in triggering the apoptosis of T-lymphocytes, which is a central pathogenic feature of HIV-mediated immune dysfunction. T-cell apoptosis is also a physiological process that regulates antigen receptor repertoire selection during homeostasis and the maturation of T- cells. We hypothesize that gp120-induced cross-talk between T-cell receptor (TCR) and chemokine receptor signaling pathways leads to apoptosis. Our preliminary data on the role of the TCR signaling components CD45 and SLP-76 in HIV-gpl20-induced apoptosis support this hypothesis. In addition, we have recently shown that cross-talk between TCR and chemokine receptor CXCR4 regulates apoptosis via a novel mechanism that is mediated by AKT/Protein Kinase B (PKB), heat shock protein-70 (HSP-70), caspase-1 and RIP2 (caspase recruitment domain-containing serine/threonine kinase). To analyze mechanistically how the TCR components and chemokine receptors CXCR4/CCR5 regulate gp120-induced apoptosis, we will pursue the following specific aims: Aim 1) we will assess the interaction between CD45 and CXCR4/CCR5 signaling molecules by defining the domain of CD45 and characterizing the CD45 signaling responsible for apoptosis. Aim 2) we will perform structural and functional analyses of the TCR-mediated downstream effector SLP-76 that mediates Ca2+dependent apoptotic pathways. Aim 3) we will analyze the role of the AKT/HSP-70 apoptotic pathway that may lead to the induction of forkhead transcription factors, and will characterize the activation of caspase-1 and its regulation by RIP2. We are also exploring innovative strategies to inhibit gp120-induced apoptosis. In this regard, we have shown that a novel protein, Slit, which binds to the Robo receptor and modulates CXCR4 function can inhibit gp120-induced apoptosis. Aim 4) we will identify which domains in the Slit/Robo complex regulate the observed anti-apoptotic effects. These studies are designed to identify apoptotic signaling molecules and effector pathways involved in T-cell loss, and thus to provide novel therapeutic targets to combat immune deficiency in AIDS.

描述（由申请人提供）：HIV-Envelope蛋白GP120在触发T-淋巴细胞的凋亡中起关键作用，这是HIV介导的免疫功能障碍的中心致病特征。 T细胞凋亡也是一个生理过程，可以调节体内稳态期间选择抗原受体曲目的选择和T-细胞成熟。我们假设GP120诱导的T细胞受体（TCR）和趋化因子受体信号通路之间的串扰会导致凋亡。我们关于TCR信号成分CD45和SLP-76在HIV-GPL20诱导的凋亡中的作用的初步数据支持了这一假设。此外，我们最近表明，TCR和趋化因子受体CXCR4之间的串扰可以通过一种新型机制调节凋亡，该机制由Akt/蛋白质激酶B（PKB）介导，热休克蛋白70（HSP-70），caspase-1，caspase-1和RIP2（caspase ronain ronain ronain ronain ronain-Contain-Contain-Contain-Contain-Contain-Contain-Contain-Contain-Contain-Contain-Contains-Containe-Containe-Containe threonine seronine seronine Kinase kinase）。为了从机械上分析TCR成分和趋化因子受体CXCR4/CCR5如何调节GP120诱导的凋亡，我们将追求以下具体目的：目标1）我们将通过定义CD45的域，并使CD45的域来评估CD45和CCR5信号分子之间的相互作用。目标2）我们将对介导Ca2+依赖性凋亡途径的TCR介导的下游效应子SLP-76进行结构和功能分析。目标3）我们将分析Akt/Hsp-70凋亡途径的作用，该途径可能导致叉状转录因子的诱导，并将表征Caspase-1的激活及其通过RIP2的调节。我们还正在探索抑制GP120诱导的凋亡的创新策略。在这方面，我们已经表明，与机器人受体结合并调节CXCR4功能的新型蛋白质SLIT可以抑制GP120诱导的细胞凋亡。目标4）我们将确定缝隙/机器人复合物中的哪些结构域调节观察到的抗凋亡作用。这些研究旨在鉴定涉及T细胞损失的凋亡信号分子和效应子途径，从而提供新颖的治疗靶标，以打击艾滋病中的免疫缺陷。