Immunomodulation of nicotine in HIV-1Tg rat brain

尼古丁对 HIV-1Tg 大鼠脑的免疫调节作用

• 批准号: 10378566
• 负责人: SULIE L. CHANG
• 金额: $ 34.78万
• 依托单位: SETON HALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378566
• 关键词: Affect; Anti-Inflammatory Agents; Astrocytes; Behavioral; Biological; Blood; Brain; Brain region; CRISPR/Cas technology; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Development; Disease; Disease Progression; Dose; Female; Gender; Gene Expression; General Population; Genes; Genetic; Genomics; Goals; HIV; HIV Infections; HIV-1; Hippocampus (Brain); Homeostasis; Immune; Immune response; Immunity; Immunofluorescence Immunologic; Immunotherapeutic agent; Individual; Infection; Inflammation; Inflammatory Response; Interleukin-1 alpha; Interleukins; Lead; Legal patent; Maintenance; Mediating; Medical; Microglia; Modeling; Molecular; Neuraxis; Neurons; Nicotine; Nicotinic Receptors; Pathology; Pathway interactions; Patients; Prefrontal Cortex; Production; Proteins; RNA; Rat Strain F344; Rattus; Regimen; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Rodent Model; Route; Series; Signal Pathway; Smoke; Smoker; Smoking; Stains; System; Techniques; Testing; Therapeutic; Tissues; Tobacco smoke; Tobacco smoking behavior; Transgenic Animals; Transgenic Organisms; Viral Proteins; Virus Replication; addiction; antiretroviral therapy; base; cigarette smoking; cytokine; desensitization; experimental study; genome-wide; immunoregulation; inflammatory modulation; interest; interferon regulatory factor-7; macrophage; male; neuroinflammation; next generation sequencing; nicotine exposure; nicotine treatment; nicotine use; receptor function; receptor-mediated signaling; relative cost; response; targeted sequencing; transcriptome sequencing; treatment duration; treatment strategy

Project Summary: As one of the key active ingredients of tobacco smoke, nicotine exerts its actions primarily on the nicotinic acetylcholine receptors (nAChRs), which are expressed on neurons, microglia, and other cells in the central nervous system (CNS). Activation of nAChRs by nicotine has various potential therapeutic immune benefits, including modulation of inflammatory responses, maintenance of immune homeostasis, and regulation of expression of pro- and anti-inflammatory factors. However, smokers have a higher rate of HIV disease progression and behavioral and cognitive complications, with differences seen between male and female smokers. It has been suggested that prolonged exposure to nicotine in HIV patients through cigarette smoking might decrease the expression and desensitize the activation of nAChRs, which could dampen nicotine's ability to mediate immune responses. During the past several years, we have conducted a series of behavioral and molecular studies using a rodent HIV-1 transgenic (HIV-1Tg) rat model to study various medical issues, including immunity, associated with HIV patients receiving combined anti-retroviral therapy (cART). We used this HIV-transgenic rat model to determine the effects of nicotine on brain function in the presence of HIV-1 proteins and found that chronic treatment with nicotine can restore the expression of many genes altered by the HIV-1 viral proteins in signaling pathways involved in immunity and other neuronal systems. In addition, we found that expression of various nAChR subunits, especially α6, β3, and β4, and immune-related genes, such as interferon regulatory factor 7 (IRF7) and interleukin-1α (IL-1α), differ greatly in HIV-1Tg rats compared with F344 controls. Our findings indicate that HIV-1 proteins greatly impact CNS immunity as well as nAChR function and alter the responsiveness to nicotine in certain immune-related and nAChR-mediated signaling pathways. Based on these findings, we hypothesize that there are significant interactions between nicotine and HIV-1 proteins that affect the immune response to nicotine in the brain of HIV-1-positive individuals. To test this hypothesis, we propose the following three aims. Aim 1 is to determine the interactive effects of nicotine and HIV viral proteins on microglia and macrophages in the brain as well as cytokine production in the blood and brain of the HIV-1Tg rat. Aim 2 is to compare the interactive effects of nicotine and HIV-1 viral proteins on gene expression in three brain regions of male and female HIV-1Tg rats using RNA-seq analysis. Aim 3 is to characterize specific genes and pathways that mediate the effects of the interaction between nicotine and HIV- 1 viral proteins using various molecular techniques, including CRISPR gene editing. The proposed studies represent the first application of next-generation sequencing technique in combination with conventional molecular approaches to investigate the modulatory effects of chronic use of nicotine on CNS immunity in the presence of HIV-1 viral proteins. By combining both genomic and molecular approaches, our studies will be comprehensive and free of subjective bias and assure the value of the data for the development of new strategies for treating HIV-1 patients who use nicotine.

项目概要： 尼古丁作为烟草烟雾的关键活性成分之一，其作用主要针对烟碱类物质。 乙酰胆碱受体 (nAChR)，在中枢神经元、小胶质细胞和其他细胞上表达 尼古丁激活 nAChR 具有多种潜在的治疗免疫益处， 包括调节炎症反应、维持免疫稳态以及调节 然而，吸烟者感染艾滋病毒的几率较高。 进展以及行为和认知并发症，男性和女性之间存在差异 有人认为，艾滋病毒患者通过吸烟而长期接触尼古丁。 可能会降低 nAChR 的表达并降低其激活的敏感性，从而抑制尼古丁的能力 在过去的几年里，我们进行了一系列的行为和免疫反应。 使用啮齿动物 HIV-1 转基因 (HIV-1Tg) 大鼠模型进行分子研究，以研究各种医学问题， 包括免疫，与接受联合抗逆转录病毒治疗（cART）的 HIV 患者有关。 这种 HIV 转基因大鼠模型用于确定在 HIV-1 存在的情况下尼古丁对大脑功能的影响 并发现长期使用尼古丁治疗可以通过以下方式恢复许多基因的表达： 此外，我们还研究了参与免疫和其他神经系统的信号通路中的 HIV-1 病毒蛋白。 发现各种 nAChR 亚基的表达，特别是 α6、β3 和 β4 以及免疫相关基因，例如 HIV-1Tg 大鼠中的干扰素调节因子 7 (IRF7) 和白细胞介素 1α (IL-1α) 与对照组相比差异很大 我们的研究结果表明，F344 蛋白极大地影响 CNS 免疫以及 nAChR。 在某些免疫相关和 nAChR 介导的信号传导中发挥作用并改变对尼古丁的反应 基于这些发现，我们发现尼古丁和尼古丁之间存在显着的相互作用。 HIV-1 蛋白影响 HIV-1 阳性个体大脑中对尼古丁的免疫反应。 假设，我们提出以下三个目标 目标 1 是确定尼古丁和尼古丁的相互作用。 大脑中小胶质细胞和巨噬细胞上的 HIV 病毒蛋白以及血液和细胞中细胞因子的产生 目标 2 是比较尼古丁和 HIV-1 病毒蛋白对 HIV-1Tg 大鼠大脑的相互作用。 使用 RNA-seq 分析雄性和雌性 HIV-1Tg 大鼠三个大脑区域的基因表达。 表征介导尼古丁和艾滋病毒之间相互作用的影响的特定基因和途径 1 病毒蛋白使用各种分子技术，包括 CRISPR 基因编辑。 代表了新一代测序技术与传统测序技术相结合的首次应用 分子方法研究长期使用尼古丁对中枢神经系统免疫的调节作用 HIV-1病毒蛋白的存在 通过结合基因组和分子方法，我们的研究将是 全面且无主观偏见，确保数据对于新产品开发的价值 治疗使用尼古丁的 HIV-1 患者的策略。

项目成果

Bi-directional Acceleration of Alcohol Use and Opioid Use Disorder.

酒精使用和阿片类药物使用障碍的双向加速。

• 发表时间: 2019
• 期刊: Journal of drug and alcohol research
• 作者: Huang,Wenfei;Penaherrera,ErikaP;Desir,DanaikaF;Gamarro,DominickL;Cottrell,Jessica;Chu,Tinchun;Chang,SulieL
• 通讯作者: Chang,SulieL

Meta-Analysis of APP Expression Modulated by SARS-CoV-2 Infection via the ACE2 Receptor.

• DOI: 10.3390/ijms23031182
• 发表时间: 2022-01-21
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Caradonna A;Patel T;Toleska M;Alabed S;Chang SL
• 通讯作者: Chang SL

Meta-Analysis of the Mechanisms Underlying COVID-19 Modulation of Parkinson's Disease.

• DOI: 10.3390/ijms241713554
• 发表时间: 2023-08-31
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

The Neuroimmune Pharmacology of SARS-CoV-2.

• DOI: 10.1007/s11481-021-10038-z
• 发表时间: 2021-12
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Kumar S;Yelamanchili S;Seth P;Bidlack JM;Pendyala G;Maggirwar S;Chang SL
• 通讯作者: Chang SL

Kinases: Understanding Their Role in HIV Infection.

• DOI: 10.4236/wja.2019.93011
• 发表时间: 2019-09-01
• 期刊: World journal of AIDS
• 作者: De Martini, William;Rahman, Roksana;Chang, Sulie L
• 通讯作者: Chang, Sulie L