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.

项目摘要： 作为烟草烟雾的主要活性成分之一，尼古丁主要在烟碱上发挥作用 乙酰胆碱受体（NACHR），在中央的神经元，小胶质细胞和其他细胞上表达 神经系统（CNS）。尼古丁对NACHR的激活具有各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 促和抗炎因子的表达。但是，吸烟者的艾滋病毒疾病发生率更高 进展，行为和认知并发症，男性和女性之间存在差异 吸烟者。有人建议通过吸烟长期暴露于艾滋病毒患者中的尼古丁 可能会降低表达并使NACHR的激活脱敏，这可能会抑制尼古丁的能力 介导免疫反应。在过去的几年中，我们进行了一系列行为和 使用啮齿动物HIV-1转基因（HIV-1TG）大鼠模型的分子研究研究各种医学问题， 包括免疫力，与接受抗逆转录病毒疗法联合的HIV患者有关（CART）。我们使用了 这种HIV转基因大鼠模型，以确定尼古丁在HIV-1的存在下对脑功能的影响 蛋白质并发现尼古丁的慢性治疗可以恢复许多基因的表达 与免疫学和其他神经元系统有关的信号通路中的HIV-1病毒蛋白。另外，我们 发现各种NACHR亚基的表达，尤其是α6，β3和β4，以及与免疫相关的基因，这种表达 作为干扰素调节因子7（IRF7）和白介素1α（IL-1α），在HIV-1TG大鼠中不同于不同 F344控件。我们的发现表明，HIV-1蛋白极大地影响CNS免疫力以及NACHR 在某些免疫相关和NACHR介导的信号传导中功能并改变对尼古丁的反应性 途径。基于这些发现，我们假设尼古丁与 HIV-1蛋白会影响HIV-1阳性个体大脑中对尼古丁的免疫激素。测试这个 假设，我们提出以下三个目标。目标1是确定尼古丁和 大脑中的小胶质细胞和巨噬细胞上的HIV病毒蛋白以及血液中的细胞因子产生 HIV-1TG大鼠的大脑。 AIM 2是比较尼古丁和HIV-1病毒蛋白对 使用RNA-Seq分析，男性和雌性HIV-1TG大鼠的三个大脑区域的基因表达。目标3是 表征特定基因和途径，介导尼古丁与HIV之间相互作用的影响 1使用各种分子技术（包括CRISPR基因编辑）的病毒蛋白。提出的研究 代表下一代测序技术的首次应用，结合常规 分子方法研究了尼古丁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，没有主观偏见，并确保数据的价值用于开发新的 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

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

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

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