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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要虽然现代疗法已使超过 3700 万艾滋病毒感染者的体验接近正常预期寿命并将其转化为可控制的慢性疾病，神经认知障碍仍然是一个尚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所贡献。神经炎症，而神经炎症会加剧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和慢性炎症有惊人的相似之处。感染可能会增加患神经退行性疾病的风险。神经炎症、神经变性和宿主对微生物病原体的免疫是免疫激酶富含亮氨酸重复激酶 2 (LRRK2) 与调节抗病毒细胞因子活性有关。赋予对分枝杆菌感染的易感性，突变的 LRRK2 是最常见的单基因突变神经退行性疾病帕金森病的病因该提案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，以确定 LRRK2 在病毒发病机制和神经炎症中的功能并评估其治疗潜力。猕猴 SIV 感染 HIV 模型，该提案旨在解决以下基本问题： SIV 感染促进 LRRK2 表达，以及 LRRK2 缺失如何影响 SIV 发病机制和宿主我们研究发现 LRRK2 通过调节抗病毒作用促进 HIV 发病机制。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 感染对免疫力的影响。循环免疫群体和胃肠道中 LRRK2 基因表达和蛋白质水平的纵向表达接下来，我们将在大脑中的单个时间点动态表达 LRRK2。使用体内和离体方法评估 LRRK2 抑制对宿主对 SIV 反应的影响。该项目获得的数据将揭示 LRRK2 在抗病毒免疫激活和为未来研究调查导致病毒诱发的因素生成初步数据拟议的研究和指导职业发展计划将在杜兰大学进行。国家灵长类动物中心 (TNPRC) 在病毒专家 Tracy Fisher 和 Ronald Veazey 博士的指导下 TNPRC 是 NHP 生物医学的国家资源。在病毒发病机制和治疗干预方面具有悠久的卓越研究历史。 TNPRC 对培训和指导有着坚定的承诺，这通过广泛的财政、努力来证明。为早期阶段培养丰富多样的培训环境 K01 提供的指导支持和投入时间将进一步推进 Vail 博士的职业目标。成为研究宿主病原体相互作用的独立研究者和 NHP 研究员。