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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

基本信息

批准号：
9789952
负责人：
Shelli Farhadian
金额：
$ 19.41万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9789952
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 genomic data genomic tools immune activation interest monocyte 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

项目摘要

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.

项目总结/文摘