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 尽管联合抗逆转录疗法（ART）取得了重大进展，但感染持续感染的成年人仍在继续 患有慢性免疫激活（包括神经认知）的病毒病毒病毒病害患病率。 确实，成年人的神经认知障碍的患病率保持不变 艺术时代：估计有50％的病毒学抑制HIV的成年人某种形式的神经认知 损伤。 迄今为止的研究。 专注于CSF生物标志物或CSF免疫细胞流式囊肿，但研究受到限制 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流行的机会 中枢神经系统免疫激活和下游神经元损伤，含有罕见的髓样子集。 候选人已经开发了可靠的管道，以便在该档案中归档单一脑脊液（CSF）免疫细胞 转录水平，并已成功使用技术来识别CSF中罕见的Cellaru子集 提出了与小胶质细胞一致的基因表达模式。 将利用这些Athods分析CSF分析CSF成人Volult没有HIV 疾病，表征已治疗期间中枢神经系统中的新型细胞种群。 CNS免疫激活以精致的细节，包括区分HIV感染的细胞种群 艺术有可能为残留神经系统损害提供治疗干预的批判目标 在艾滋病毒治疗期间。 首席研究员是一名医师科学家，具有专门的培训旅馆神经疾病和 神经遗传学的博士学位。 传染病的后遗症，特别关注Hib感染的神经学。 K23培训计划提供了候选人的指导和课程，以构成特定的专业人士 执行该项目并独立在她的领域中，包括：1的专业知识所必需的。 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 3。领导独立的，以患者为导向的研究的技能。 Farhadian Hass组建了一个主要的指导团队，由神经hiv，神经免疫学专家组成， 和生物信息学。