Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection

HIV/SIV 感染中大麻素调节神经炎症的表观遗传机制

• 批准号: 10656263
• 负责人: Siddappa N Byrareddy
• 金额: $ 69.69万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656263
• 关键词: 2-arachidonylglycerol; Aberrant DNA Methylation; Acute; Affect; Agonist; Alzheimer' s Disease; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Attention; Autopsy; Basal Ganglia; Blood; Brain; CASP1 gene; CNR1 gene; CNR2 gene; CXCL10 gene; Cannabidiol; Cannabinoids; Cells; Central Nervous System; Cerebrospinal Fluid; Chronic; Colon; CpG Islands; Crystallins; DNA; DNA Methylation; Data; Decision Making; Development; Disease; Disease Progression; Endocannabinoids; Endoplasmic Reticulum; Epigenetic Process; Epithelium; Ethanolamines; Event; Gene Expression; Generations; Genes; HIV; HIV-associated neurocognitive disorder; Heat shock proteins; Heritability; IRF1 gene; Immunologics; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferons; Intestines; Knowledge; Lipids; Longevity; Lysine; Macaca; Macaca mulatta; Measures; Mediating; Memory; Mental Depression; MicroRNAs; Microglia; Mitosis; Molecular; Movement; Multiple Sclerosis; Nature; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Oxidative Stress; Oxidoreductase; PPAR gamma; Parkinson Disease; Pathogenesis; Patients; Penetration; Peripheral; Persons; Pharmaceutical Preparations; Play; Production; Proteins; Research; Residual state; Risk; Role; SIV; STAT2 gene; Serum Markers; Signal Transduction; Site; Symptoms; TRPV1 gene; Testing; Tetrahydrocannabinol; Therapeutic; Time; Up-Regulation; Viral; Viral reservoir; Virus Replication; WFS1 gene; Wolfram Syndrome; antiretroviral therapy; cannabinoid treatment; chemokine; combinatorial; comorbidity; cytokine; daughter cell; ds-DNA; endocannabinoid signaling; endogenous cannabinoid system; endoplasmic reticulum stress; fatty acid amide hydrolase; glial activation; immune activation; immune function; immunomodulatory strategy; immunoregulation; innovation; lymph nodes; mRNA Expression; monocyte; nervous system disorder; neuroAIDS; neuroinflammation; prevent; promoter; protein expression; receptor; response; simian human immunodeficiency virus

ABSTRACT HIV associated neurological disorder (HAND), a major comorbidity affecting about 30-50% of patients receiving suppressive anti-retroviral therapy is characterized by difficulties with attention, concentration, decision making and memory, depression and slowed movements. Although chronic activation of brain microglia is proposed to drive HAND, the molecular mechanisms remain ill defined. Emerging evidence has shown that epigenetic mechanisms involving aberrant DNA methylation may significantly contribute to the pathogenesis of multiple sclerosis, Parkinson’s and Alzheimer’s disease. Nevertheless, the role of DNA methylation specifically in HIV induced monocyte/microglia activation remains unknown. The fact that epigenetic marks are heritable and passed on to several generations of daughter cells during mitosis might explain a potential mechanism causing monocyte/microglial activation that may in turn help maintain persistent neuroinflammation in cART treated patients. Our preliminary studies identified significant upregulation of proinflammatory interferon stimulated and chemokine genes in basal ganglia and marked alterations in DNA methylation of CpG islands in promoters of genes associated with inflammatory response, apoptosis, dsDNA damage response and oxidative stress in colonic epithelium of chronically SIV-infected macaques, respectively. More importantly, chronic cannabinoid treatment to ART naïve SIV-infected rhesus macaques prevented proinflammatory gene expression in brain and epigenetic alterations suggesting their immense therapeutic potential for attenuating neuroinflammation and reduced HAND related symptoms. In the proposed studies, we will for the first time investigate changes in DNA methylation associated with delta-9-tetrahydrocannabinol (THC), cannabidiol, JWH133 (CB2R agonist) induced suppression of monocyte/microglial activation through the course of SIV infection. Further, we will determine the effect of combination anti-retroviral treatment (cART) in conjunction with chronic cannabinoid treatments on epigenetic alterations, viral reservoir, inflammation and endogenous cannabinoid levels in the blood and cerebrospinal fluid. Finally, we will investigate the receptor mediated and molecular mechanisms by which THC blocks endoplasmic reticulum stress, a key event in the onset of neurodegenerative diseases. The proposed research is highly innovative and applies state of the art immunological and molecular approaches to fill a significant gap in our understanding of the epigenetic mechanisms associated with HAND. As cannabinoids have shown great promise for the treatment of neurological disorders, the proposed studies are necessary, as it will provide a fundamental understanding of the epigenetic and endocannabinoid mechanisms underlying their anti- inflammatory effects. Finally, the results will have important therapeutic implications for immune modulation in not only HIV but also other chronic neuroinflammatory diseases.

抽象的 HIV 相关神经系统疾病 (HAND) 是一种主要合并症，影响约 30-50% 接受治疗的患者 抑制性抗逆转录病毒治疗的特点是注意力、集中力、决策困难 以及记忆、抑郁和行动迟缓。尽管大脑小胶质细胞的慢性激活被认为 驱动手，分子机制仍然不明确。新出现的证据表明表观遗传 涉及异常 DNA 甲基化的机制可能对多种疾病的发病机制有显着影响 硬化症、帕金森病和阿尔茨海默病。然而，DNA 甲基化在 HIV 中的作用 诱导的单核细胞/小胶质细胞激活仍然未知。表观遗传标记是可遗传的，并且 在有丝分裂过程中传递给几代子细胞可能解释了导致 单核细胞/小胶质细胞的激活可能反过来有助于维持 cART 治疗中的持续性神经炎症 患者。我们的初步研究发现促炎干扰素刺激和 基底节趋化因子基因和启动子中 CpG 岛 DNA 甲基化的显着改变 与炎症反应、细胞凋亡、双链DNA损伤反应和氧化应激相关的基因 分别是慢性感染 SIV 的猕猴的结肠上皮。更重要的是，慢性大麻素 对首次接受 ART 感染 SIV 的恒河猴进行治疗可预防大脑中促炎基因的表达 表观遗传改变表明它们在减轻神经炎症和 减少手相关症状。在拟议的研究中，我们将首次研究 DNA 的变化 与 delta-9-四氢大麻酚 (THC)、大麻二酚、JWH133（CB2R 激动剂）诱导相关的甲基化 在 SIV 感染过程中抑制单核细胞/小胶质细胞的激活。此外，我们将确定 联合抗逆转录病毒治疗（cART）与慢性大麻素治疗的效果 表观遗传改变、病毒库、炎症和血液中的内源性大麻素水平 脑脊液。最后，我们将研究 THC 的受体介导和分子机制。 阻断内质网应激，这是神经退行性疾病发病的关键事件。拟议的 研究具有高度创新性，并应用最先进的免疫学和分子方法来填补 我们对与 HAND 相关的表观遗传机制的理解存在重大差距。由于大麻素具有 显示出治疗神经系统疾病的巨大前景，拟议的研究是必要的，因为它将 提供对其抗-表观遗传和内源性大麻素机制的基本了解 炎症作用。最后，这些结果将对免疫调节具有重要的治疗意义。 不仅是艾滋病毒，还有其他慢性神经炎症性疾病。