Role of LRRK2 in immunity in a nonhuman primate model of SIV

LRRK2 在 SIV 非人灵长类动物模型免疫中的作用

• 批准号: 10693552
• 负责人: Krystal Vail
• 金额: $ 19.37万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693552
• 关键词: ANXA5 gene; Address; Agonist; Attenuated; Bacterial Infections; Basal Ganglia; Biological; Biological Assay; Biological Response Modifiers; Biomedical Research; Blood; Bone Marrow; Brain; Cell Death; Cells; Chronic; Chronic Disease; Clinical; Corpus striatum structure; DNA Sequence Alteration; Data; Dedications; Development Plans; Disease; Disease model; Encephalitis; Enrollment; Environment; Enzyme-Linked Immunosorbent Assay; Euthanasia; Exhibits; Flow Cytometry; Fresh Tissue; Future; Gastrointestinal tract structure; Gene Expression; Gene Proteins; Genes; Goals; Grant; Gut Mucosa; HIV; HIV Infections; HIV-1; Health; Hippocampus; Homeostasis; Human; Immune; Immune response; Immunity; Immunohistochemistry; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Interferon Type I; Intestines; K-Series Research Career Programs; Knowledge; LRRK2 gene; Leukocytes; Life Expectancy; Link; Lymphocyte; Macaca; Macaca mulatta; Macrophage; Mentors; Mentorship; Messenger RNA; Microglia; Mitochondria; Modeling; Modernization; Monitor; Morphology; Mucosal Immunity; Mus; Mutate; Mutation; Mycobacterium Infections; Nerve Degeneration; Neurocognitive Deficit; Neurodegenerative Disorders; Neuroglia; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Phosphorylation; Phosphotransferases; Play; Poly I-C; Population; Predisposition; Primates; Production; Propidium Diiodide; Proteins; RNA; Recording of previous events; Regulation; Reporting; Research; Research Personnel; Resources; Rest; Risk; Role; SIV; Severities; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Tuberculosis; Viral; Viral Load result; Viral Pathogenesis; Virus Diseases; Western Blotting; antiretroviral therapy; antiviral immunity; career; career development; chemokine; chronic infection; cytokine; experience; frontal lobe; immune activation; immunoregulation; improved; in vivo; inhibitor; mitochondrial metabolism; neuroinflammation; neurotoxic; nonhuman primate; oxidative damage; pathogen; pathogenic microbe; pharmacologic; response; seroconversion; seropositive; tat Protein

Project Summary While modern therapy has enabled the more than 37 million people living with HIV to experience near normal life expectancy and transformed it into a manageable chronic disease, neurocognitive impairment remains an unresolved clinical concern. Increasing evidence indicates that chronic systemic immune activation contributes to neuroinflammation, and neuroinflammation promotes the severity of neurodegenerative diseases. Intriguingly, viral-induced neuroinflammation has striking similarities to neurodegenerative disease, and chronic infection may increase the risk of developing neurodegenerative disease. One factor linked to neuroinflammation, neurodegeneration, and host immunity against microbial pathogens is the immune kinase leucine rich repeat kinase 2 (LRRK2). LRRK2 has been implicated in modulating antiviral cytokine activity, conferring susceptibility to mycobacterial infection, and mutated LRRK2 is the most common monogenetic cause of the neurodegenerative disorder Parkinson’s disease. The long-term objectives of this proposal are to extend the observation that LRRK2 modulates antiviral immunity during bacterial infection to determine the function of LRRK2 in viral pathogenesis and neuroinflammation and assess its therapeutic potential. Using a macaque SIV infection model for HIV, this proposal seeks to address the fundamental questions of whether SIV infection promotes LRRK2 expression, and how loss of LRRK2 impacts SIV pathogenesis and the host immune response. We hypothesize that LRRK2 contributes to HIV pathogenesis through regulation of antiviral immunity. To test this, we will use a non-human primate (NHP) model to assess the impact of SIV infection on LRRK2 gene expression and protein levels longitudinally in circulating immune populations and gastrointestinal tract, and at a single time point in the brain as LRRK2 is dynamically expressed in these tissues. Next, we will assess the impact of LRRK2 inhibition on host response to SIV using both in vivo and ex vivo approaches. The data obtained by this project will shed light on the function of LRRK2 in antiviral immune activation and generate preliminary data for future studies investigating factors contributing to viral-induced neuroinflammation. The proposed study and Mentored Career Development Plan will be conducted at Tulane National Primate Center (TNPRC) under the guidance of Drs. Tracy Fisher and Ronald Veazey, experts in viral induced neuroinflammation and SIV pathogenesis. The TNPRC is a national resource for NHP biomedical research with a long history of research excellence in viral pathogenesis and therapeutic intervention. The TNPRC has a strong commitment to training and mentorship demonstrated by extensive financial, effort- based, and programmatic support to cultivate a rich and diverse training environment for early-stage investigators. The mentored support and dedicated time provided by the K01 will further Dr. Vail’s career goals of becoming an independent investigator and NHP researcher studying host pathogen interactions.

项目摘要 虽然现代疗法使超过3700万人艾滋病毒的人能够接近正常 预期寿命并将其转变为可控制的慢性疾病，神经认知障碍仍然是 未解决的临床问题。越来越多的证据表明慢性全身免疫激活有助于 神经炎症和神经炎症促进了神经退行性疾病的严重程度。 有趣的是，病毒引起的神经炎症与神经退行性疾病具有惊人的相似性，慢性 感染可能会增加患神经退行性疾病的风险。链接到的一个因素 神经炎症，神经变性和宿主对微生物病原体的免疫史是免疫激酶 Leucine富含重复激酶2（LRRK2）。 LRRK2已暗示在调节抗病毒细胞因子活性时， 会议对分枝杆菌感染和突变的LRRK2的敏感性是最常见的单基因遗传学 神经退行性疾病帕金森氏病的原因。该提议的长期目标是 扩展了LRRK2在细菌感染期间调节抗病毒免疫的观察结果 LRRK2在病毒发病机理和神经炎症和评估其治疗潜力中的功能。使用 该提案旨在解决有关HIV的猕猴SIV感染模型，旨在解决是否是否 SIV感染促进LRRK2表达，LRRK2的丧失如何影响SIV发病机理和宿主 免疫反应。我们假设LRRK2通过调节抗病毒有助于HIV发病机理 免疫。为了测试这一点，我们将使用非人类灵长类动物（NHP）模型来评估SIV感染对 LRRK2基因表达和蛋白质水平在循环的免疫吞吐量和胃肠道中纵向 在大脑中的一个时间点，作为LRRK2在这些组织中动态表达。接下来，我们会的 使用体内和体内方法评估LRRK2抑制对宿主对SIV的响应的影响。这 该项目获得的数据将阐明LRRK2在抗病毒免疫激活中的功能和 生成未来研究的初步数据研究因素导致病毒诱导的因素 神经炎症。拟议的研究和指导的职业发展计划将在Tulane进行 国家灵长类动物中心（TNPRC）在博士的指导下。特雷西·费舍尔（Tracy Fisher）和罗纳德·维阿西（Ronald Veazey），病毒专家 诱导神经炎症和SIV发病机理。 TNPRC是NHP生物医学的国家资源 在病毒发病机理和治疗干预方面卓越研究历史的研究。这 TNPRC对培训和心态有坚定的承诺，以大量的财务，努力证明 - 基于培养早期阶段丰富多样的培训环境的程序化支持 调查人员。 K01提供的事项支持和专门的时间将进一步进一步 成为独立研究者和NHP研究人员，研究宿主病原体相互作用。