Understanding the cellular basis for persistent immune activation in the central nervous system during virologically suppressed HIV

了解病毒学抑制艾滋病毒期间中枢神经系统持续免疫激活的细胞基础

• 批准号: 10000209
• 负责人: Shelli Farhadian
• 金额: $ 19.07万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000209
• 关键词: Adult; Affect; Big Data; Bioinformatics; Biological; Biological Markers; Blood; Blood Cells; Cell Lineage; Cells; Cerebrospinal Fluid; Chronic; Communicable Diseases; Communities; Computer Analysis; Cytometry; Data; Dendritic Cells; Detection; Disease; Doctor of Philosophy; Exhibits; Face; Flow Cytometry; Future; Gene Expression; Gene Expression Profile; Gene Proteins; Genetic Transcription; Genomic approach; Genomics; Goals; HIV; HIV Infections; HIV therapy; HIV-1; Head; Immune; Immune system; Immunology; Impairment; Individual; Infection; Inflammation; Light; Long-Term Effects; Mediating; Mediator of activation protein; Mentors; Mentorship; Methods; Microglia; Morbidity - disease rate; Myelogenous; Myeloid Cells; Neopterin; Nerve Degeneration; Neuraxis; Neurocognitive Deficit; Neurodegenerative Disorders; Neurologic; Neurologic Effect; Neuronal Injury; Neurons; Participant; Pathway interactions; Patients; Physicians; Plasma; Population; Prevalence; Principal Investigator; Process; RNA; Research; Research Personnel; Residual state; Scientist; Specific qualifier value; Techniques; Therapeutic Intervention; Training; Transcript; Viral; Virus; Virus Diseases; Virus Replication; antiretroviral therapy; base; career; cell type; computational pipelines; genomic data; genomic tools; immune activation; interest; monocyte; neuroAIDS; neurocognitive disorder; neurofilament; neurogenetics; neuroimaging; neuroimmunology; new therapeutic target; novel; patient oriented research; prevent; programs; single-cell RNA sequencing; skills; targeted treatment; therapy development; tool; virology; volunteer

PROJECT SUMMARY/ABSTRACT Despite major advances in combination antiretroviral therapy (ART), adults living with HIV infection continue to suffer from high rates of morbidities associated with chronic immune activation, including neurocognitive impairment. Indeed, the prevalence of neurocognitive disorders in adults with HIV remains unchanged in the ART era: an estimated 50% of adults with virologically suppressed HIV have some form of neurocognitive impairment. Understanding the cellular basis for persistent CNS immune activation is thus critical for reducing neurological morbidities in the growing population of adults with HIV on treatment. Studies to date have focused on CSF biomarkers or CSF immune cell flow cytometry, but these studies are limited by the need to pre-specify markers of interest, thus missing the opportunity to identify de novo cell populations that may drive CNS immune activation and downstream neuronal damage, including rare myeloid subsets. The candidate has developed a reliable pipeline to profile single cerebrospinal fluid (CSF) immune cells at the transcriptional level, and has successfully used this technique to identify a rare cellular subset in CSF that presents a gene expression pattern consistent with disease-associated microglia. The research proposed here will utilize these state of the art methods to analyze CSF and blood from adult volunteers with and without HIV disease, to characterize novel or rare cell populations in the CNS during treated, suppressed HIV. Defining CNS immune activation in exquisite detail, including cellular populations that distinguish HIV infection during ART, has the potential to provide critical targets for therapeutic intervention for residual neurologic impairment during HIV treatment. The principal investigator is a physician scientist, with specialized training in Neuroinfectious disease and a PhD in Neurogenetics. Her career goal is to become an independent investigator studying neurological sequelae of infectious diseases, with a special focus on neurological effects of HIV infection. The proposed K23 training plan will provide the candidate with mentorship and coursework to build specific expertise necessary to execute the proposed project and become independent in her field, including expertise in: 1. Immunology and Neuro-infectious diseases 2. “Big data” genomics and associated computational analysis, and 3. Skills necessary to head an independent, patient-oriented research program. To achieve these goals, Dr. Farhadian has assembled a primary mentoring team consisting of experts in Neuro-HIV, Neuroimmunology, and Bioinformatics.

项目摘要/摘要 尽管联合抗逆转录病毒疗法（ART）取得了重大进展，但感染HIV感染的成年人仍在 患有与慢性免疫激活相关的病因率高，包括神经认知 损害。确实，艾滋病毒成年人的神经认知障碍的患病率在 艺术擦除：估计有50％的病毒学抑制HIV的成年人具有某种形式的神经认知 损害。因此，了解持久性中枢神经系统免疫激活的细胞基础对于降低至关重要 治疗中艾滋病毒成年人不断增长的人群的神经病病毒。迄今为止的研究有 专注于CSF生物标志物或CSF免疫细胞流式细胞术，但这些研究受到需要的限制 预先指定的感兴趣的标记，因此错过了识别可能驱动的从头细胞种群的机会 中枢神经系统免疫激活和下游神经元损伤，包括罕见的髓样子集。 候选人已经开发了可靠的管道，以剖析单一脑脊液（CSF）免疫细胞 转录水平，并已成功使用该技术来识别CSF中罕见的细胞子集 提出与疾病相关小胶质细胞一致的基因表达模式。这里提出的研究 将利用这些最先进的方法来分析有或没有艾滋病毒的成年志愿者的CSF和血液 疾病，以治疗后抑制艾滋病毒的中枢神经系统中的新颖或罕见的细胞群体来表征疾病。定义 CNS免疫激活以独家的细节激活，包括区分HIV感染的细胞种群 ART，有可能为残留神经系统损害的治疗干预提供关键目标 在艾滋病毒治疗期间。 首席研究者是一名物理科学家，对神经感染性疾病进行专门培训， 神经遗传学的博士学位。她的职业目标是成为研究神经系统的独立研究者 传染病的后遗症，特别关注HIV感染的神经系统作用。提议 K23培训计划将为候选人提供指导和课程，以建立特定的专业知识 执行拟议项目并在其领域独立的必要条件，包括：1。 免疫学和神经感染疾病2。“大数据”基因组学和相关的计算分析，以及 3。领导独立的，以患者为导向的研究计划所需的技能。为了实现这些目标，博士 法哈迪安（Farhadian 和生物信息学。