Role of miRNAs in Methamphetamine/HIV-mediated Immune Activation

miRNA 在甲基苯丙胺/HIV 介导的免疫激活中的作用

• 批准号: 10357940
• 负责人: WENZHE HO
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357940
• 关键词: Address; Astrocytes; Biological Markers; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chronic; Clinical; Disease Progression; Flagellin; HIV; HIV Infections; HIV-associated neurocognitive disorder; HLA-DR Antigens; Impairment; In Vitro; Individual; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Measures; Mediating; Methamphetamine; MicroRNAs; Neuronal Injury; Neurons; Peptidoglycan; Plasma; Ribosomal DNA; Role; Small RNA; Study Subject; T-Lymphocyte; Validation; brain tissue; central nervous system injury; clinically relevant; clinically significant; drug of abuse; immune activation; in vivo; inhibitor; macrophage; methamphetamine effect; methamphetamine use; methamphetamine user; microbial; monocyte; neurotoxic; systemic inflammatory response; transcriptome sequencing

Abstract Chronic immune activation is a major factor of HIV disease progression. Bacterial products of microbial translocation from the gut are likely to be a cause of systemic immune activation in chronic HIV infection. However, the mechanism(s) responsible for chronic immune activation remain to be determined. Given that drugs of abuse contribute greatly to HIV infection, it is crucial to study whether use of methamphetamine (METH), one of the most commonly abused drugs among HIV-infected individuals, is associated with HIV infection-related systemic inflammation and chronic immune activation. We hypothesize that METH use result in inflammation and immune activation through induction of the inflammatory and neurotoxic miRNAs, which facilitate HIV replication and the BBB/CNS injury. We propose three specific aims to address this hypothesis. In Aim 1, we will determine the plasma levels of several key microbial components and immune activation markers in METH users with or without HIV infection. We will also measure the plasma levels of inflammatory/neurotoxic miRNAs in these subjects; In Aim 2, we will study whether monocytes and T lymphocytes from METH users express higher levels of the inflammatory/neurotoxic miRNAs than those from non-METH users. We will also investigate whether METH has synergetic effect with the microbial products on enhancing HIV infection of macrophages and whether the cells from METH users are more susceptible to HIV infection than those from control subjects; In Aim 3, we will examine the effects of METH and/or HIV on the expression of inflammatory and neurotoxic miRNAs in the brain tissues and CSF from subjects with or without HIV-associated neurocognitive disorder (HAND). In addition, we will mechanistically investigate the role of inflammatory/neurotoxic miRNAs (let-7, miR-17, -20a, -21, -132, -146a) in the BBB and neuronal injury. These proposed studies with combinational in vitro (Aim 3), ex vivo (Aim 2), and in vivo (Aims 1, 2, 3) approaches are clinically relevant and significant, and will determine previously unrecognized biomarkers and mechanisms for METH use-mediated systemic inflammation/immune activation and impairment of the BBB/CNS.

摘要