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: 10374058
• 负责人: Lishomwa C Ndhlovu
• 金额: $ 80.76万
• 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/10374058
• 关键词: Acute; Address; Adult; Age; Age-Years; Alzheimer' s Disease; American; Biological; Blood; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Central Nervous System Degenerative Diseases; Clinical; 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 antiretroviral; HIV-associated cognitive impairment; HIV-associated neurocognitive disorder; Image; Immune; Immunologic Markers; Immunologics; Impaired cognition; Individual; Inflammation; Inflammatory Response Pathway; Intervention; Knowledge; Link; Masks; Mediator of activation protein; Methods; Methylation; Microglia; Molecular; Myeloid Cells; NR4A2 gene; Nerve Degeneration; Neuropsychological Tests; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Phenotype; Play; Population; Positioning Attribute; Predisposition; Process; Property; Publishing; Rare Diseases; Resolution; Role; Site; Sorting - Cell Movement; Specimen; THBS1 gene; Technology; Testing; 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; macrophage; methylome; mild cognitive impairment; monocyte; multidisciplinary; multiple omics; neuroinflammation; new technology; novel; recruit; single cell analysis; single cell technology; single-cell RNA sequencing; 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 疾病预防控制中心估计，2012年艾滋病毒感染艾滋病毒的四分之一年龄在55岁以上。接下来 一年，这些人将年满60岁，进入了阿尔茨海默氏病（AD）的年龄人群 对于临床医生而言，这是一个独特的差异。因为多达一半的患有艾滋病毒经验的人 艾滋病毒或相关因素的认知障碍，掩盖的可能性，从而延迟诊断 早期广告很重要。与温和认知能力区分艾滋病毒相关的神经认知障碍（手） AD损伤阶段（MCI-AD）是老年神经hiv中最紧迫的问题之一。当前的手 疾病没有就此问题提供指导。已发表的工作表明了独特的可能性 通过神经心理学的常见输入有助于诊断分类的表型 测试和结构成像，但可能还不够。许多研究强调了 手和AD的发病机理中的髓样细胞（单核细胞，巨噬细胞和小胶质细胞）。在这个 我们建议利用细胞类型特异性特异性和剪切的应用来利用表观遗传学的力量 边缘单细胞技术，以定义与手的区分和重叠的免疫生物标志物与 60岁以上的个人MCI-AD。该应用将检验以下假设 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的血液中的循环单核细胞存在 与年龄与年龄匹配的正常艾滋病毒+年龄在60岁以上的人相比 逆转录病毒疗法。我们进一步认为，全面定义与手动相关的单核细胞类型将有助于 在区分MCI-AD的个体同时也定义了基本神经病的过程中 每种疾病的机制。特定目的是目标1：检查单核细胞表观遗传表型 在60多年的个人中，早期MCI-AD与手相比，分别在认知上正常 年龄匹配的艾滋病毒+个人抑制艺术。目标2利用单细胞分辨率技术 询问可用于比较和对比的独特单核细胞亚群表型 用MCI-AD和手。目标3：验证原代单核细胞中的MCI-AD和手动相关特征 并定义位点特异性甲基化事件的功能后果。两个主要结果是 该提议所获得的知识的期望：（1）揭示生物学途径以了解 手和MCI-AD的发病机理。 2）应对将手与轻度区分开的挑战 老年神经hiv中AD引起的认知障碍。