Characterization of cocaine induced signaling pathways that enhances HIV transcription

可卡因诱导的增强 HIV 转录的信号通路的表征

• 批准号: 10399877
• 负责人: Mudit Tyagi
• 金额: $ 0.98万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399877
• 关键词: Aging; Anti-HIV Therapy; Cell Aging; Cell surface; Cells; Chronic; Cocaine; Complication; Cytokine Activation; Diagnostic tests; Drug Addiction; Effectiveness; Functional disorder; Gene Expression; Genetic Transcription; Goals; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Immunologic Markers; Individual; Inflammation; Inflammatory; Investigation; Length; Link; Lymphoid Cell; Myeloid Cells; NF-kappa B; Nerve Degeneration; Neuraxis; Neurocognitive; Neurocognitive Deficit; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Premature aging syndrome; Process; Production; Proteins; Regimen; Severities; Signal Pathway; Site; Surface Antigens; Telomerase; Therapeutic Intervention; Transcript; Up-Regulation; cocaine exposure; cocaine use; comorbidity; cytokine; drug of abuse; exhaustion; immune activation; improved; interest; nervous system disorder; new therapeutic target; telomere

TITLE: Assessing the impact of cocaine and HIV in accelerating aging process Accelerated aging is a complication of HIV infection despite the effectiveness of highly active antiretroviral therapy (HAART or ART). This is due, in part, to HIV-associated neurological disorders (HAND) which are caused mainly by the ongoing immune activation and inflammation in the CNS. There is considerable evidence that suggests an additive or synergistic effect of cocaine on the persistence and severity of neurocognitive dysfunction in HIV- infected patients. Therefore, the relationship between drugs of abuse, such as cocaine, HIV infection, neurodegeneration and accelerated aging is of particular interest. Overall goal of the proposed investigation is to understand the underlying mechanisms through which cocaine use further accelerates the aging process in HIV infected individuals by enhancing immune activation and inflammation. Currant anti-HIV therapy is unable to restrict HIV protein production. Certain HIV proteins are toxic, especially to the CNS, as they stimulate pro-inflammatory cytokines and immune activation. Cocaine further enhance HIV protein production. The investigation proposed in this application will establish that cocaine accelerates the aging process by comparing cocaine treated and untreated HIV-infected both lymphoid and myeloid cells. Results will be confirmed in PBMCs of HIV-infected subjects with or without cocaine exposure. The following aims are proposed to confirm and quantify the impact of cocaine in promoting premature aging: Aim 1A: Analysis of cell surface markers of immune activation and inflammation, selectively triggered by cocaine Aim 1B: Investigate the potential impact of cocaine exposure on cell senescence Aim 1C: Determine the cocaine effect on cell exhaustion Aim 2: Define the plasma markers of immune activation and inflammation following cocaine use Aim 3: Examine the impact of cocaine on telomere length, telomerase transcript, protein and activity. The investigation proposed in this application will establish that cocaine accelerates the aging process by comparing cocaine-using HIV infected subjects with those not using cocaine.

标题：评估可卡因和艾滋病毒在加速衰老过程中的影响 加速老化是艾滋病毒感染的并发症，尽管高效抗逆转录病毒治疗有效 （HAART或ART）。这部分是由于艾滋病毒相关的神经系统疾病（HAND）， 免疫激活和中枢神经系统炎症的影响有大量证据表明， 可卡因对HIV感染者神经认知功能障碍的持续性和严重性的叠加或协同作用， 感染的病人。因此，可卡因等药物滥用与艾滋病毒感染， 神经变性和加速老化是特别令人感兴趣的。 拟议调查的总体目标是了解可卡因 通过增强免疫激活， 炎症目前的抗HIV治疗无法限制HIV蛋白质的产生。某些HIV蛋白质 有毒，特别是对CNS，因为它们刺激促炎细胞因子和免疫激活。可卡因 进一步提高HIV蛋白质的产量。本申请中提出的调查将确定， 可卡因加速老化过程通过比较可卡因治疗和未经治疗的艾滋病毒感染者， 淋巴样和髓样细胞。结果将在HIV感染受试者的PBMC中确认， 可卡因暴露 提出了以下目标，以确认和量化可卡因在促进过早衰老方面的影响： 目的1A：分析免疫活化和炎症的细胞表面标志物，选择性地由 可卡因 目的1B：研究可卡因暴露对细胞衰老的潜在影响 目的1C：确定可卡因对细胞耗竭的影响 目的2：确定可卡因使用后免疫激活和炎症的血浆标志物 目的3：研究可卡因对端粒长度、端粒酶转录、蛋白质和活性的影响。 本申请中提出的研究将确定可卡因通过以下方式加速衰老过程： 将使用可卡因的HIV感染者与不使用可卡因的HIV感染者进行比较。