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.

项目概要 CDC 估计，2012 年，四分之一的美国人艾滋病毒感染者年龄超过 55 岁。 今年，这些人将超过 60 岁，进入阿尔茨海默病 (AD) 的年龄人口 对临床医生来说成为一个明显的区别。因为多达一半的艾滋病毒感染者经历过 HIV 或相关因素造成的认知障碍，掩盖并因此延迟诊断的可能性 公元早期是很重要的。区分 HIV 相关神经认知障碍 (HAND) 和轻度认知障碍 AD 损伤阶段 (MCI-AD) 是老年神经 HIV 中最紧迫的问题之一。当前手牌 疾病分类学并未就此问题提供指导。已发表的工作表明不同的可能性 表型有助于利用神经心理学常用的输入进行诊断分类 测试和结构成像，但这些可能还不够。许多研究强调了 骨髓细胞（单核细胞、巨噬细胞和小胶质细胞）在 HAND 和 AD 发病机制中的作用。在这个 我们建议利用表观遗传学的力量，利用细胞类型特定的特征和切割- 边缘单细胞技术来定义 HAND 与 HAND 的区别和重叠免疫生物标志物 60 岁以上个体的 MCI-AD。该应用程序将测试以下假设：稀有群体 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特征定义，存在于 HAND 与 60 岁以上、年龄匹配、认知正常的 HIV+ 个体相比，接受抑制性抗 逆转录病毒疗法。我们进一步认为，全面定义这种与 HAND 相关的单核细胞类型将有助于 区分 HAND 和 MCI-AD 个体，同时定义基本的神经致病性 每种疾病的机制。具体目标是目标 1：检查单核细胞表观遗传表型 与 HAND 相比，60 岁以上患有早期 MCI-AD 的个体的认知能力正常 年龄匹配的 HIV+ 个体接受抑制性 ART。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 与 MCI-AD 和 HAND。目标 3：验证原代单核细胞中的 MCI-AD 和 HAND 相关特征 并定义位点特异性甲基化事件的功能后果。两个主要成果是 从该提案获得的知识中期望：（1）揭示生物学途径以理解 HAND 和 MCI-AD 的发病机制。 2) 解决区分 HAND 和 Mild 的挑战 老年神经 HIV 患者因 AD 导致的认知障碍。