Brain Structural and Functional Connectome in HIV-Associated Neuroinflammation

HIV 相关神经炎症中的脑结构和功能连接组

基本信息

批准号：
10844919
负责人：
GIOVANNI SCHIFITTO
金额：
$ 38.26万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-20 至 2025-04-30
项目状态：
未结题

项目摘要

The parent grant RO1 MH118020 utilizes novel methodologies to assess the longitudinal changes in the trajectory of the brain structural and functional connectivity in people with HIV (PWH) compared to healthy controls (HC) in the context of intermediaries of inflammation and coagulopathy (soluble CD14 and CD163, D- dimer, soluble tissue factor and TF+ monocytes). Further, the parent grant also aims to assess the mediation effect of structural and functional connectivity and cerebral cortical thickness on specific cognitive domains. Preliminary data from the parent grant show that non-classical monocytes (NCMs) in PWH correlate with cognitive impairment. NCMs reach the highest levels in those with cerebral small vessel disease (CSVD) compared to no CSVD. Furthermore, monocyte TF expression is increased in PWH compared to HC. In this administrative supplement, we propose to extend our current investigations to study the effect of aging and HIV on non-classical monocyte subpopulations and TF expression in the context of CSVD, brain connectivity, and cognition. Our approach is to take advantage of the baseline clinical, imaging, and stored specimens of the 220 study participants enrolled to address the Specific Aims listed below: Aim 1: To assess the effect of aging and HIV on non-classical monocyte subtypes. We hypothesize that aging and HIV will have additive or synergistic effects on NCMs' cellular states characterized by pathways that release inflammatory factors and promote monocyte-endothelial cell interaction, an important step in monocyte transmigration to the brain parenchyma. NCMs subtypes will be assessed via Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq). The experiments will be conducted in PWH and healthy control study participants aged ≤40 and ≥50 without CSVD. Aim 2: To characterize the effect of cellular states of non-classical monocytes in CSVD. We hypothesize that PWH with CSVD will have unique subtypes of monocytes which will be assessed using CITE-seq and will be characterized using computational tools developed by our group and others. Specifically, CITE-seq will be performed on PWH and healthy control study participants aged ≥50, with and without CSVD. Aim 3: To assess whether cellular states of non-classical monocytes mediate alterations in brain connectivity and whether this is reflected in cognitive performance. We hypothesize that NCMs subtypes promote neuroinflammation, contributing to CSVD and altered brain connectivity. The clinical correlate of CSVD and altered brain connectivity is cognitive impairment. We will use our previously described PathCellNet approach along with Weighted Gene Correlation Network Analysis (WGCNA) optimized for single- cell analysis to define NCMs subtype-specific gene signatures that can be correlated with the clinical measurements. We will also use structural equation modeling (SEM) to understand the causal effect of NCMs on cognitive impairment.

父授予RO1 MH118020利用新方法来评估与健康相比，艾滋病毒（PWH）的大脑结构和功能连通性对照（HC）在炎症和凝血病中间人的背景下（可溶性CD14和CD163，d- 二聚体，固体组织因子和TF+单核细胞）。此外，父母赠款还旨在评估调解结构和功能连通性以及脑皮质厚度对特定认知结构域的影响。父母赠款的初步数据表明，PWH中的非经典单核细胞（NCMS）与认知障碍。在患有脑小血管疾病（CSVD）的患者中，NCM达到最高水平。与没有CSVD相比。此外，与HC相比，PWH中的单核细胞TF表达增加。在这种行政补充中，我们建议扩展当前的调查以研究衰老的影响在非古典单核细胞亚群和CSVD背景下的HIV和TF表达上连通性和认知。我们的方法是利用基线临床，成像和存储 220名研究参与者的标本已入学，以解决以下列出的具体目的：目标1：评估衰老和HIV对非经典单核细胞亚型的影响。我们假设这一点衰老和HIV将对NCMS的细胞状态增加或协同作用，其特征是以途径为特征释放炎症因子并促进单核细胞 - 内皮细胞相互作用，这是单核细胞的重要一步转移到脑实质。 NCMS亚型将通过细胞索引评估通过测序（cite-seq）进行转录组和表位。实验将在PWH和没有CSVD的健康对照研究参与者≤40和≥50。目标2：表征CSVD中非经典单核细胞的细胞状态的作用。我们假设使用CSVD的PWH将具有独特的单核细胞亚型，将使用Cite-Seq评估，并将使用我们的小组和其他人开发的计算工具来表征。具体来说，cite-seq将是在有或没有CSVD的情况下，在PWH和健康对照研究的参与者上进行。目标3：评估非经典单核细胞的细胞状态是否介导了大脑的改变连通性以及这是否反映在认知表现中。我们假设NCMS子类型促进神经炎症，导致CSVD并改变大脑连通性。临床相关 CSVD和大脑连通性改变是认知障碍。我们将使用我们先前描述的 Pathcellnet方法以及对单次的加权基因相关网络分析（WGCNA）细胞分析以定义可以与临床相关的NCMS亚型特异性基因标志测量。我们还将使用结构方程建模（SEM）来了解NCM的因果关系关于认知障碍。