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

基本信息

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
项目类别：
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

项目摘要

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对加速衰老过程的影响尽管高效抗逆转录病毒治疗有效，加速衰老仍然是艾滋病毒感染的并发症（HAART 或 ART）。这在一定程度上是由于艾滋病毒相关的神经系统疾病（HAND）造成的，这主要是由于中枢神经系统中持续的免疫激活和炎症。有大量证据表明可卡因对 HIV 患者神经认知功能障碍的持续性和严重程度的叠加或协同作用感染的患者。因此，滥用药物（例如可卡因）与艾滋病毒感染之间的关系，神经退行性变和加速衰老尤其令人感兴趣。拟议调查的总体目标是了解可卡因的潜在机制使用通过增强免疫激活和进一步加速艾滋病毒感染者的衰老过程炎。目前的抗 HIV 治疗无法限制 HIV 蛋白的产生。某些 HIV 蛋白质是有毒，尤其是对中枢神经系统，因为它们会刺激促炎细胞因子和免疫激活。可卡因进一步增强HIV蛋白的产生。本申请中提出的调查将确定通过比较可卡因治疗和未治疗的艾滋病毒感染者，可卡因加速衰老过程淋巴和骨髓细胞。结果将在 HIV 感染者的 PBMC 中得到证实，无论是否有可卡因暴露。提出以下目标来确认和量化可卡因促进过早衰老的影响：目标 1A：分析免疫激活和炎症的细胞表面标志物，选择性触发可卡因目标 1B：研究可卡因暴露对细胞衰老的潜在影响目标 1C：确定可卡因对细胞衰竭的影响目标 2：确定可卡因使用后免疫激活和炎症的血浆标志物目标 3：检查可卡因对端粒长度、端粒酶转录本、蛋白质和活性的影响。本申请中提出的研究将证实可卡因通过以下方式加速衰老过程：将使用可卡因的艾滋病毒感染者与不使用可卡因的受试者进行比较。