Harnessing Single Cell Epigenome-wide profiling of Myeloid cells to Compare and Contrast Alzheimer's from HIV-Associated Cognitive Dysfunction

利用骨髓细胞的单细胞表观基因组分析来比较和对比 HIV 相关认知功能障碍引起的阿尔茨海默病

• 批准号: 10795252
• 负责人: Lishomwa C Ndhlovu
• 金额: $ 12.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10795252
• 关键词: Acute; Address; Adult; Age; Age Years; Alzheimer' s Disease; American; Biological; Blood; Cell physiology; Cells; Central Nervous System Degenerative Diseases; Clinical; Cognition; Cognitive; Complex; DISC1 gene; DNA Methylation; DNA methylation profiling; Data; Detection; Diagnostic; Disease; Early Diagnosis; Elderly; Environmental Risk Factor; Epigenetic Process; Event; Genes; Genetic; Genome; HIV; HIV Infections; HIV-associated cognitive impairment; HIV-associated neurocognitive disorder; Immune; Immunologic Markers; Immunologics; Impaired cognition; Individual; Inflammation; Inflammatory Response Pathway; Intervention; Knowledge; Link; Macrophage; Mediator; Methods; Methylation; Microglia; Molecular; Myeloid Cells; NR4A2 gene; Nerve Degeneration; Neuropsychological Tests; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Phenotype; Population; Positioning Attribute; Predisposition; Process; Property; Publishing; Rare Diseases; Resolution; Role; Site; Sorting; Specimen; THBS1 gene; Technology; Testing; Viremia; Work; aging population; antiretroviral therapy; base; brain dysfunction; cell type; cognitive performance; cohort; disease classification; epigenetic profiling; epigenome; experience; geriatric neuroHIV; histone modification; immune activation; improved; innovation; methylome; mild cognitive impairment; monocyte; multidisciplinary; multiple omics; neuroinflammation; new technology; novel; recruit; single cell analysis; single cell technology; single-cell RNA sequencing; structural imaging; treatment strategy

Project Summary The CDC estimated that one-quarter of Americans living with HIV were over the age of 55 in 2012. By next year, these individuals will be over age 60, entering into the age demographic where Alzheimer's disease (AD) becomes a distinct differential for clinicians. Because up to one-half of people living with HIV experience cognitive impairment from HIV or related factors, the likelihood for masking and thus delaying the diagnosis of early AD is substantial. Differentiating HIV-associated Neurocognitive Disorder (HAND) from the Mild Cognitive Impairment stage of AD (MCI-AD) is one of the most pressing issues in geriatric neuroHIV. Current HAND nosology does not provide guidance on this issue. Published work suggests the likelihood for distinct phenotypes that would facilitate diagnostic sorting with commonly available inputs from neuropsychological testing and structural imaging, but these may not be sufficient. Many studies highlight the importance of myeloid cells (monocytes, macrophages and microglia) in the pathogenesis of both HAND and AD. In this application we propose to harness the power of epigenetics utilizing cell type specific signatures and cutting- edge single cell technologies to define distinguishing and overlapping immune biomarkers of HAND from the MCI-AD in individuals over 60 years of age. This application will test the hypothesis that a rare population of circulating monocytes in blood defined by an indelible epigenetic profile related to the CNS are present in HAND compared to age-matched cognitively normal HIV+ individuals over age 60 on suppressive anti- retroviral therapy. We further posit that comprehensively defining this HAND-related monocyte cell type will aid in distinguishing HAND from individuals with MCI-AD while also defining fundamental neuropathogenic mechanisms of each disease. The specific aims are Aim 1: To examine monocyte epigenetic phenotypes in individuals over 60 years with early MCI-AD compared to HAND and, separately, cognitively normal age-matched HIV+ individuals on suppressive ART. Aim 2 To utilize single cell resolution technology to interrogate unique monocyte subpopulation phenotypes that can be used to compare and contrast with MCI-AD and HAND. Aim 3: To validate MCI-AD and HAND related signatures in primary monocytes and define functional consequences of site-specific methylation events. Two major outcomes are expected from the knowledge gained by this proposal: (1) to reveal biological pathways to understand the pathogenesis of HAND and MCI-AD. and 2) address the challenges of distinguishing HAND from Mild Cognitive Impairment due to AD in geriatric neuroHIV.

项目摘要 美国疾病控制与预防中心估计，2012年，四分之一的美国艾滋病毒携带者年龄在55岁以上。到下一步 年，这些人将超过60岁，进入阿尔茨海默病(AD)的年龄人口统计 对临床医生来说是一个明显的区别。因为多达一半的艾滋病毒携带者经历过 艾滋病毒或相关因素造成的认知损害，掩盖并因此延误诊断的可能性 公元早期是相当可观的。HIV相关性神经认知障碍(手)与轻度认知障碍的鉴别 阿尔茨海默病的损害阶段(MCI-AD)是老年神经性HIV最紧迫的问题之一。当前手 病因学不在这个问题上提供指导。发表的研究表明，不同的 使用神经心理学的常用输入来促进诊断分类的表型 测试和结构成像，但这些可能还不够。许多研究都强调了 髓系细胞(单核细胞、巨噬细胞和小胶质细胞)在手部和AD发病机制中的作用。在这 应用我们建议利用表观遗传学的力量，利用细胞类型特定的签名和切割- 边缘单细胞技术，以定义区分和重叠的手部免疫生物标记物 MCI-AD适用于60岁以上的个人。这个应用程序将检验这样的假设：一种稀有的 血液中的循环单核细胞由与中枢神经系统相关的不可磨灭的表观遗传学特征定义，存在于 Hand与年龄匹配的60岁以上认知正常HIV+者的抑制性抗-DNA抗体比较 逆转录病毒疗法。我们进一步认为，全面定义这种与手相关的单核细胞类型将有助于 在区分手部与MCI-AD患者的同时定义基础神经致病 每种疾病的发病机制。具体目标是1：检测单核细胞表观遗传表型 60岁以上早期MCI-AD患者与手部和认知正常个体的比较 与艾滋病病毒携带者年龄相匹配的抑制艺术。目标2利用单细胞分辨技术 询问可用于比较和对比的独特的单核细胞亚群表型 使用MCI-AD和Hand。目的3：在原代单核细胞中验证MCI-AD和手部相关信号 并定义特定部位甲基化事件的功能后果。两个主要结果是 从这项提议中获得的知识期望：(1)揭示生物学途径，以理解 Hand与MCI-AD的发病机制。和2)解决区分手部和手部的挑战 老年性神经HIV中AD所致的认知功能障碍。