Role of microRNAs in B-cell dysfunction in HIV/SIV infection

microRNA 在 HIV/SIV 感染 B 细胞功能障碍中的作用

基本信息

批准号：
10060222
负责人：
Mahesh Mohan
金额：
$ 94.28万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10060222
关键词：
Acetylation Acute Address Anti-Inflammatory Agents Antibodies Antibody Response Antiinflammatory Effect Apoptosis Attenuated Autoimmune Diseases Autoimmune Process Autoimmune Responses B cell differentiation B-Cell Activation B-Lymphocytes Biological Assay Blood CD4 Positive T Lymphocytes Cannabinoids Cell Survival Cell physiology Cells Chronic Data Defect Disease Disease Progression Down-Regulation Functional disorder Gastrointestinal tract structure Gene Expression Regulation Generations Genetic Transcription Goals HIV HIV Infections Homeostasis Hyperactive behavior Immune Immune Targeting Immunologics Immunosuppressive Agents Impairment In Vitro Infection Inflammation Intestines Lead Link Luciferases Lymphocyte Lymphomagenesis MS4A1 gene Macaca Macaca mulatta Marijuana Mediating Memory Memory B-Lymphocyte MicroRNAs Molecular Morbidity - disease rate Multiple Sclerosis Pathogenesis Patients Plasma Cells Play Population Post-Transcriptional Regulation Property Quantitative Reverse Transcriptase PCR RNA Interference Regulation Reporter Research Rheumatoid Arthritis Role SIRT1 gene SIV System Systemic Lupus Erythematosus T-Cell Depletion Testing Tetrahydrocannabinol Therapeutic Time Up-Regulation Vaccines Virus Replication antiretroviral therapy base chronic inflammatory disease cytokine high risk immune activation immunoregulation improved inhibitor/antagonist knock-down lymph nodes marijuana use mortality novel p65 plasma cell differentiation prevent public health relevance restoration therapeutic target transcription factor transcriptome

项目摘要

DESCRIPTION (provided by applicant): B-cell dysfunction is a hallmark of HIV/SIV infection that begins very early in infection even before CD4 T cell depletion. Increasing evidence suggests that heightened B-cell activation, lack of memory B-cell restoration and impaired vaccine induced antibody responses persists even in patients receiving suppressive anti- retroviral therapy. Even though our understanding of B-cell dynamics in HIV/SIV infection has significantly improved, the molecular mechanisms underlying B-cell dysfunction remain poorly understood. In addition to cytokines and transcription factors, recent studies show miRNA-mediated gene regulation to be critical for B- cell differentiation, maturation, activation and autoimmune responses. Extensive studies in autoimmune diseases associated with B-cell defects have revealed a causative role for microRNAs in disease pathogenesis resulting in their identification as promising therapeutic targets. However, the role of miRNAs in HIV induced B-cell dysfunction is lacking. Our preliminary studies for this application identified significant dysregulation of miRNAs linked to B-cell activation and lymphomagenesis in purified B-cells from chronically SIV-infected macaques. Interestingly and more importantly, chronic THC treatment to SIV-infected macaques markedly inhibited their expression suggesting their immense therapeutic potential for attenuating immune (B-cell) activation and slowing disease progression. Based on our strong preliminary data demonstrating that miRNA expression is dysregulated in B-cells in HIV/SIV infection, we hypothesize that this leads to B-cell dysfunction which contributes to immune activation and HIV disease progression. Further, we hypothesize that chronic 9- THC treatment may reduce inflammation, restore immune (B-cell) function, and slow HIV/SIV disease progression by modulating miRNA expression. A major goal of this application is to identify miRNA mechanisms associated with B-cell dysfunction and cannabinoid mediated suppression of B-cell activation. The project has three specific aims: 1) Test the hypothesis that miR-34a and miR-155 targeting of SIRT1 leads to enhanced acetylated-p65 and acetylated-FOXO3a expression, causing B-cell hyperactivity and apoptosis, respectively. 2) Identify miRNA mechanisms of cannabinoid induced suppression of B-cell activation in blood, lymph nodes, and intestine at three different time points following SIV infection. 3) Determine the effect of combination anti-retroviral treatment (cART) in conjunction with chronic 9-THC administration on inflammation, chronic immune activation, viral replication, miRNA expression, SIRT1 levels, B-cell activation and apoptosis. The proposed research is novel and applies state of the art immunological and molecular approaches to address a significant gap in our understanding of the post-transcriptional mechanisms underlying B-cell dysfunction. Additionally and more importantly, the results will deepen our understanding of the mechanisms underlying the anti-inflammatory effects of cannabinoids and have important therapeutic implications for targeted immune modulation in HIV and other autoimmune diseases with B-cell defects.

描述（由适用提供）：B细胞功能障碍是HIV/SIV感染的标志，甚至在CD4 T细胞耗竭之前就开始在感染的早期开始。越来越多的证据表明，即使在接受抑制性抗网状病毒疗法的患者中，即使在接受抑制性抗网状病毒疗法的患者中，B细胞激活，缺乏记忆B细胞恢复和疫苗诱导的抗体反应受损。即使我们对HIV/SIV感染中B细胞动力学的理解已显着改善，但B细胞功能障碍的分子机制仍然鲜为人知。除了细胞因子和转录因子外，最近的研究表明，miRNA介导的基因调节对于B细胞分化，成熟，激活和自身免疫反应至关重要。与B细胞缺陷相关的自身免疫性疾病的广泛研究表明，MicroRNA在疾病发病机理中起着灾难性的作用，导致其鉴定为有希望的治疗靶标。但是，缺乏miRNA在HIV诱导的B细胞功能障碍中的作用。我们针对此应用的初步研究确定了与来自镀铬SIV感染的猕猴纯化的B细胞中B细胞激活和淋巴细胞化相关的miRNA失调。它们的免疫学潜力减弱免疫（B细胞）激活和疾病进展减慢。基于我们强大的初步数据，表明在HIV/SIV感染中B细胞中miRNA表达失调，我们假设这会导致B细胞功能障碍，这有助于免疫激活和HIV疾病进展。此外，我们假设慢性9-THC治疗可以通过调节miRNA表达来降低感染，恢复免疫（B细胞）功能以及慢速HIV/SIV疾病进展。该应用的主要目的是确定与B细胞功能障碍和大麻素介导的B细胞激活抑制相关的miRNA机制。该项目具有三个特定的目的：1）检验以下假设：SIRT1的miR-34a和miR-155靶向SIRT1的靶向增强了乙酰化P65和乙酰化 - 纤维化 - 福克斯3A的表达，从而导致B细胞多动和凋亡。 2）在SIV感染后三个不同的时间点下，在血液，淋巴结和肠中抑制大麻素诱导的B细胞活化的miRNA机制。 3）确定抗逆转录病毒治疗（CAR）与慢性9-THC给药结合对注射，慢性免疫激活，病毒复制，miRNA表达，SIRT1水平，B细胞激活和凋亡的影响。拟议的研究是新颖的，并应用了最先进的免疫学和分子方法，以解决我们对B细胞功能障碍基础的转录后机制的理解的显着差距。此外，更重要的是，结果将加深我们对大麻素抗炎作用的机制的理解，并对HIV和其他患有B细胞缺陷的HIV和其他自身免疫性疾病的靶向免疫调节具有重要的治疗意义。