Motor Dysfunction in cART-era HIV: Neural Circuitry and Pathogenesis

cART 时代 HIV 的运动功能障碍：神经回路和发病机制

基本信息

批准号：
10251283
负责人：
Susan Morgello
金额：
$ 82.36万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251283
关键词：
Affect Aging Astrocytes Autopsy Biological Assay Blood Vessels Brain Brain region Candidate Disease Gene Cell Nucleus Cells Central Nervous System Diseases Cerebral small vessel disease Cerebrovascular Disorders ChIP-seq Chromatin Cognitive Complex Corpus striatum structure DNA Data Set Diagnostic radiologic examination Diffusion Etiology Fluorescence Functional Magnetic Resonance Imaging HIV HIV-associated neurocognitive disorder Histology Histone Acetylation Histones Image Immunohistochemistry Impairment Individual Inflammation Inflammatory Linear Regressions Magnetic Resonance Imaging Medical Microglia Midbrain structure Molecular Molecular Profiling Motor Nested PCR Neurodegenerative Disorders Neurologic Neurons Oligodendroglia Organ Donations Participant Pathogenesis Pathology Patients Pattern Population Quality of life Risk Risk Factors Sampling Sorting - Cell Movement Standardization Structure Task Performances Testing Tissues Vascular Diseases White Matter Disease antiretroviral therapy brain abnormalities cell type cerebral atrophy cerebrovascular cohort comorbidity dimensional analysis epigenome epigenomics falls genome-wide gray matter high dimensionality histone methylation imaging study insight interest monocyte motor deficit motor disorder motor impairment multimodality neural circuit neurogenomics neuroimaging neuroinflammation recruit relating to nervous system targeted treatment transcriptome transcriptome sequencing transcriptomics vascular contributions vascular risk factor white matter

项目摘要

Summary Motor dysfunction is prevalent in combination antiretroviral therapy (cART) era HIV+ populations, however, its genesis is unclear, as cerebrovascular disease is likely to contribute to its etiology. We propose to study the spectrum, underlying neural circuitry, and cell type-specific molecular signatures of HIV-associated motor dysfunction, with the following aims and hypotheses: Aim 1. Identify neural regions associated with motor impairment in HIV+ patients with and without cerebrovascular disease. 160 cART-treated subjects will be recruited to a structural and functional magnetic resonance imaging study, to test the hypothesis that the neuroanatomical basis of motor task performance will vary by motor status (normal/abnormal) and presence or absence of cerebrovascular comorbidity. For this 2x2 analysis, participants in the Manhattan HIV Brain Bank (MHBB) will form a nidus for recruitment, with multimodal assessment of motor function. These analyses will be conducted in years 1 and 2. Then, having identified regions most strongly implicated in motor dysfunction, in years 3 through 5 we will examine autopsy brains from the MHBB cohort for: Aim 2. Cell-type specific transcriptome and epigenome mapping in dorsolateral striatum, ventral midbrain, and selected gray and white matter regions of interest (ROI) as defined in aim 1 to identify molecular signatures of motor dysfunction. Our hypothesis is that the molecular genesis of motor dysfunction can be elucidated through regional and cell-type specific analysis of transcriptome and open chromatin-associated histone acetylation and methylation landscape. Specifically, that neuronal, astrocyte, and oligodendrocyte signatures in HIV+ brain regions implicated in motor function will be affected by HIV-inflammatory burden and regional cerebrovascular disease; and that motor function will be predicted by these regional changes. Fluorescence-activated nuclei sorting in neuroanatomic regions implicated in motor dysfunction will be used for cell-type specific fractions of input material for genome-scale RNA-Seq and histone ChIP-seq. In contiguous tissue, assays of HIV DNA by nested PCR, monocyte/microglial cell activation by CD68 and CD163 immunohistochemistry, and cerebral small vessel disease (CSVD) by morphometric analysis of arteriolar wall thickening, will be done. 100 MHBB HIV+ brains will be selected on the basis of cognitive profiles and vascular risk to best approximate living subjects in aim #1, along with brains accrued from imaged individuals through subsequent organ donation. 50 demographically similar HIV- brains will also be studied. Candidate genes in molecular signatures of motor dysfunction with and without vascular disease will be tested via qPCR. With these aims, we will elucidate the neural circuitry of motor dysfunction in cART-treated HIV, cerebrovascular contributions to its genesis, and characterize its regional neurogenomics. Insight into molecular alterations and targets for amelioration will be relevant to a wider spectrum of neurodegenerative disorders with vascular contributions in HIV- populations.

概括运动功能障碍在联合抗逆转录病毒治疗 (cART) 时代的 HIV+ 人群中普遍存在，然而，其发病原因尚不清楚，因为脑血管疾病可能是其病因之一。我们建议研究 HIV 相关运动的频谱、潜在神经回路和细胞类型特异性分子特征功能障碍，具有以下目标和假设：目标 1. 识别与运动相关的神经区域患有或不患有脑血管疾病的 HIV+ 患者的损伤。 160 名接受 cART 治疗的受试者将招募参加结构和功能磁共振成像研究，以检验以下假设：运动任务表现的神经解剖学基础将根据运动状态（正常/异常）和存在或不存在而变化。没有脑血管合并症。对于此 2x2 分析，曼哈顿 HIV 脑库的参与者（MHBB）将形成一个招募病灶，并对运动功能进行多模式评估。这些分析将在第一年和第二年进行。然后，确定了与运动功能障碍最密切相关的区域，在第 3 年至第 5 年，我们将对 MHBB 队列中的大脑进行尸检，以实现：目标 2. 细胞类型特异性背外侧纹状体、腹侧中脑和选定的灰白色区域的转录组和表观基因组图谱目标 1 中定义的感兴趣物质区域 (ROI)，用于识别运动功能障碍的分子特征。我们的假设运动功能障碍的分子起源可以通过区域和细胞类型来阐明转录组和开放染色质相关组蛋白乙酰化和甲基化的特异性分析景观。具体来说，HIV+大脑区域的神经元、星形胶质细胞和少突胶质细胞特征运动功能会受到HIV炎症负担和局部脑血管疾病的影响；并且运动功能将通过这些区域变化来预测。荧光激活的细胞核分选与运动功能障碍有关的神经解剖区域将用于细胞类型特定的输入部分用于基因组规模 RNA-Seq 和组蛋白 ChIP-seq 的材料。在邻近组织中，通过以下方法检测 HIV DNA：巢式 PCR、CD68 和 CD163 免疫组织化学检测单核细胞/小胶质细胞激活以及脑小血管疾病（CSVD）通过小动脉壁增厚的形态测量分析，将进行。 100 MHBB HIV+ 大脑将根据认知特征和血管风险进行选择，以最接近生活目标#1中的受试者，以及通过随后的器官捐赠从成像个体中获得的大脑。 50 人口统计上相似的艾滋病病毒大脑也将被研究。运动分子特征中的候选基因有或没有血管疾病的功能障碍将通过 qPCR 进行测试。带着这些目标，我们将阐明 cART治疗的HIV运动功能障碍的神经回路、脑血管对其发生的贡献，以及描述其区域神经基因组学特征。深入了解分子改变和改善目标将是与 HIV 人群中更广泛的神经退行性疾病相关，并伴有血管作用。