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.

项目总结:

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