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

• 批准号: 10459605
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459605
• 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; 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; 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; radiological imaging; recruit; relating to nervous system; targeted treatment; transcriptome; transcriptome sequencing; transcriptomics; vascular contributions; vascular risk factor; white matter

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 运动功能障碍在抗逆转录病毒疗法（CART）ERA HIV+种群中普遍存在 起源尚不清楚，因为脑血管疾病可能有助于其病因。我们建议研究 频谱，潜在的神经回路和与HIV相关运动的细胞类型特异性分子特异性信号 功能障碍，具有以下目的和假设：目标1。确定与运动相关的神经区域 患有和没有脑血管疾病的HIV+患者的损害。 160个手推车处理的受试者将是 招募到结构性和功能性磁共振成像研究，以检验以下假设。 运动任务性能的神经解剖学基础将因运动状态（正常/异常）和存在或存在而异 缺乏脑血管合并症。对于此2x2分析，曼哈顿艾滋病毒脑库的参与者 （MHBB）将形成招募的NIDU，并对运动功能进行多模式评估。这些分析将 在第1和2年内进行。 在第3至5年级，我们将检查MHBB队列的尸检大脑：AIM 2。细胞类型特异性 背外侧纹状体，腹中脑和选定的灰色和白色的转录组和表观基因组映射 AIM 1中定义的目标区域（ROI）以识别运动功能障碍的分子特征。我们的 假设是，可以通过区域和细胞类型阐明运动功能障碍的分子发生 转录组和开放染色质相关组蛋白乙酰化和甲基化的特定分析 景观。具体而言，HIV+脑区域中的神经元，星形胶质细胞和少突胶质细胞特征 与运动功能有关的影响将受到HIV炎症负担和区域脑血管疾病的影响； 这些区域变化将预测运动功能。荧光激活的核分类 与运动功能障碍有关的神经解剖区域将用于细胞类型的特定输入部分 基因组尺度RNA-seq和组蛋白芯片seq的材料。在连续组织中，通过 CD68和CD163免疫组织化学和脑化的嵌套PCR，单核细胞/小胶质细胞激活以及脑化 小血管疾病（CSVD）将通过小动脉壁增厚的形态分析进行。 100 MHBB HIV+大脑将根据认知概况和血管风险选择最佳生活 AIM＃1的受试者以及随后的器官捐赠从成像的个体中获得的大脑。 50 人口相似的艾滋病毒也将被研究。电动机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测试。以这些目的，我们将阐明 手推车处理的HIV中运动功能障碍的神经回路，对其起源的脑血管贡献和 表征其区域神经基因组学。对分子改变和改善目标的见解将是 与在HIV群体中具有血管贡献的神经退行性疾病的更广泛范围有关。