Gene Expression Induced by HIV-1 and Chemokine Receptor

HIV-1 和趋化因子受体诱导的基因表达

• 批准号: 6969410
• 负责人: DENNIS D. TAUB
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6969410
• 关键词: HIV envelope protein gp120; T lymphocyte; biotechnology; cell migration; chemoattractants; chemokine receptor; human immunodeficiency virus 1; human tissue; immunocytochemistry; microarray technology; pathologic process; protein structure function; receptor binding; tissue /cell culture; transcription factor; virus infection mechanism; virus protein; western blottings

Besides chemotaxis, C-X-C and C-C chemokines function as mediators in T-cell activation and in many lymphocyte biological responses. Detailed information about downstream signaling pathways is necessary to understand the role of chemokines in normal physiology and inflammation. We have built several focused cDNA chips containing approximately 3000 known human genes that are expressed and secreted by a variety of cell types including lymphoid cells and participate in cell growth, signal transduction, effector functions, CD molecules, metabolism and apoptosis. Initial studies using differential display analysis and commercial cDNA chips have demonstrated that T cells expressing either endogenous chemokine receptors or transfected chemokine receptors are induced to express a variety of known and unknown genes post ligand treatment. A number of genes have been identified including thioredoxin, CA150, flotillin, ferritin heavy chain, and various cytokines. These mRNA expression difference have since been verified by RT-PCR and Western blot analysis. Additional studies are underway examining the ability of various HIV-1 viral isolates, gp120 proteins, cytokines, and chemokines to directly induce gene expression in young and old human lymphocytes and neuronal cells. We believe that active transcriptional signals through CD4 and/or chemokine receptor molecules are required for optimal HIV-1 infectivity and propagation as well as for normal lymphocyte adhesion and migration. Using our customized human and murine cDNA and oligonucleotide microarray gene chips, we have examined the expression of over 22K known and unknown genes induced post chemokine receptor ligation or viral infection. We believe that the identification and examination of induced or suppressed genes will not only provide insight into HIV pathogenesis but may also elucidate the molecular mechanisms of inflammation and the various signaling defects observed in aged lymphocytes. We are currently confirming and characterizing several genes highly expressed in T cells after migration in response to or stimulation with SDF-1, MIP-3, RANTES, gp120 and HIV-1 virus. A greater understanding of the transcriptional signals differentially induced by the ligation of various chemokine receptors may provide a means to dissect the pathways by which these chemoattractants induce cell migration and activation as well as any host transcriptional signals important in HIV entry and replication.

除了趋化性之外，C-X-C和C-C趋化因子在T细胞活化和许多淋巴细胞生物学应答中作为介体起作用。关于下游信号通路的详细信息对于理解趋化因子在正常生理学和炎症中的作用是必要的。我们已经建立了几个集中的cDNA芯片，其中包含约3000个已知的人类基因，这些基因由包括淋巴细胞在内的各种细胞类型表达和分泌，并参与细胞生长，信号转导，效应器功能，CD分子，代谢和凋亡。使用差异显示分析和商业cDNA芯片的初步研究已经证明，表达内源性趋化因子受体或转染的趋化因子受体的T细胞在配体处理后被诱导表达多种已知和未知的基因。已经鉴定了许多基因，包括硫氧还蛋白、CA 150、flotillin、铁蛋白重链和各种细胞因子。这些mRNA表达差异已经通过RT-PCR和Western blot分析得到验证。其他研究正在进行中，检查各种HIV-1病毒分离株，gp 120蛋白，细胞因子和趋化因子直接诱导年轻和老年人淋巴细胞和神经元细胞中基因表达的能力。我们认为，通过CD 4和/或趋化因子受体分子的活性转录信号是最佳的HIV-1感染性和繁殖以及正常的淋巴细胞粘附和迁移所必需的。使用我们定制的人类和小鼠cDNA和寡核苷酸微阵列基因芯片，我们已经检查了超过22 K已知和未知基因的表达诱导后趋化因子受体连接或病毒感染。我们相信，诱导或抑制基因的鉴定和检查不仅可以深入了解HIV的发病机制，而且还可以阐明炎症的分子机制和在老年淋巴细胞中观察到的各种信号传导缺陷。我们目前正在确认和表征几个基因在T细胞迁移后高度表达，以响应或刺激SDF-1，MIP-3，RANTES，gp 120和HIV-1病毒。更好地了解不同的转录信号诱导的各种趋化因子受体的连接可能提供一种手段来解剖这些化学引诱剂诱导细胞迁移和激活的途径，以及任何主机的转录信号在HIV的进入和复制的重要。