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 CDC估计，2012年，四分之一的美国艾滋病毒感染者年龄超过55岁。到明年 这些人将超过60岁，进入阿尔茨海默病（AD） 成为临床医生的一个明显区别。因为多达一半的艾滋病毒感染者 艾滋病毒或相关因素造成的认知障碍，掩盖的可能性，从而延迟诊断， 早期AD是非常重要的。HIV相关神经认知障碍（HAND）与轻度认知障碍的区别 AD的损害期（MCI-AD）是老年神经HIV最紧迫的问题之一。当前手动 疾病分类学并不提供关于这个问题的指导。已发表的研究表明， 表型，这将有助于诊断分类与常见的输入，从神经心理学 测试和结构成像，但这些可能还不够。许多研究强调了以下方面的重要性： 骨髓细胞（单核细胞、巨噬细胞和小胶质细胞）在HAND和AD的发病机制中的作用。在这 应用，我们提出利用表观遗传学的力量，利用细胞类型特异性签名和切割- 边缘单细胞技术，以定义HAND的区别和重叠的免疫生物标志物， MCI-AD在60岁以上的个体中。这个应用程序将测试假设，一个罕见的人口， 血液中的循环单核细胞由与CNS相关的不可消除的表观遗传特征定义， HAND与年龄匹配的认知正常的60岁以上的HIV+个体相比， 逆转录病毒疗法我们进一步证实，全面定义这种HAND相关的单核细胞类型将有助于 在区分HAND与MCI-AD个体的同时， 每种疾病的机制。具体目的是目的1：检查单核细胞表观遗传表型 在60岁以上的早期MCI-AD患者中，与HAND相比，分别为认知正常的患者 年龄匹配的HIV+个体进行抑制性ART。目的2利用单细胞分辨技术 为了询问独特的单核细胞亚群表型， 与MCI-AD和手。目的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）揭示生物学途径以了解 HAND和MCI-AD的发病机制。和2）解决区分HAND和轻度的挑战 老年neuroHIV患者AD所致的认知障碍