Role of Chemokine & T-Cell Receptors in HIV Pathogenesis

趋化因子的作用

• 批准号: 7556689
• 负责人: Ramesh K. Ganju
• 金额: $ 21.59万
• 依托单位: OHIO STATE UNIVERSITY
• 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/7556689
• 关键词: 76-kDa SH2 domain-containing leukocyte protein; Acquired Immunodeficiency Syndrome; Antigen Receptors; Apoptosis; Apoptotic; Binding; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 Receptors; CXCR4 gene; Calcium; Caspase; Caspase-1; Cell Maturation; Complex; Data; Development; Drosophila sli protein; Event; HIV; HIV Envelope Protein gp120; Heat shock proteins; Heat-Shock Proteins 70; Homeostasis; Immune; Immune System Diseases; Knowledge; LCP2 gene; Lead; Link; Mediating; PTPRC gene; Pathogenesis; Pathway interactions; Physiological Processes; Play; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; RIPK2 gene; Receptor Signaling; Regulation; Research Design; Role; Signal Pathway; Signal Transduction; Signaling Molecule; T-Cell Receptor; T-Lymphocyte; Therapeutic; Work; apoptosis in lymphocytes; base; chemokine; chemokine receptor; expectation; forkhead protein; innovation; novel; novel therapeutics; receptor; receptor function; therapeutic target

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包膜蛋白gp 120在触发T淋巴细胞凋亡中起关键作用，T淋巴细胞凋亡是HIV介导的免疫功能障碍的主要致病特征。T细胞凋亡也是在T细胞的稳态和成熟期间调节抗原受体库选择的生理过程。我们假设gp 120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导致细胞凋亡。我们关于TCR信号成分CD 45和SLP-76在HIV-gp 120诱导的细胞凋亡中的作用的初步数据支持了这一假设。此外，我们最近发现TCR和趋化因子受体CXCR 4之间的相互作用通过一种新的机制调节细胞凋亡，该机制由AKT/蛋白激酶B（PKB）、热休克蛋白-70（HSP-70）、半胱天冬酶-1和RIP 2（含半胱天冬酶募集结构域的丝氨酸/苏氨酸激酶）介导。为了分析TCR组分和趋化因子受体CXCR 4/CCR 5如何调节gp 120诱导的细胞凋亡，我们将追求以下具体目标：目的1）我们将通过定义CD 45的结构域和表征负责细胞凋亡的CD 45信号传导来评估CD 45和CXCR 4/CCR 5信号传导分子之间的相互作用。目的2）我们将对TCR介导的下游效应子SLP-76进行结构和功能分析，该效应子介导Ca 2+依赖性凋亡途径。目的3）分析AKT/HSP-70凋亡通路中可能导致叉头转录因子诱导的作用，并将表征caspase-1的激活及其受RIP 2的调节。我们也在探索创新的策略来抑制gp 120诱导的细胞凋亡。在这方面，我们已经表明，一种新的蛋白质，Slit，它结合到Robo受体和调节CXCR 4功能可以抑制gp 120诱导的细胞凋亡。目的4）我们将鉴定Slit/Robo复合物中的哪些结构域调节所观察到的抗凋亡作用。这些研究旨在鉴定参与T细胞损失的凋亡信号分子和效应子途径，从而提供新的治疗靶点以对抗艾滋病中的免疫缺陷。