Changes in monocyte transcriptome as a predictor of cognitive decline in WTC responders: a longitudinal study

单核细胞转录组的变化作为世贸中心响应者认知能力下降的预测因子：一项纵向研究

• 批准号: 10459190
• 负责人: SEAN CLOUSTON
• 金额: $ 49.74万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459190
• 关键词: Changes; monocyte; transcriptome; predictor; cognitive

ABSTRACT Now nineteen years after 9/11, a high proportion of World Trade Center (WTC) responders show elevated mental and physical health effects that include a higher than expected burden of mild cognitive impairment (MCI), an early sign of Alzheimer’s disease (AD) or a related dementia (ADRD). Because the potential for neurodegenerative diseases as indicated by MCI are concerning, there is a critical need to understand the pathogenesis of the disorder and identify biomarkers to facilitate early intervention before irreversible changes to the brain occur. Our pilot work revealed that monocyte subpopulation showed the largest changes in transcriptome associated with MCI and the differentially expressed (DE) genes were enriched in pathways related to neuroinflammation. These findings are in line with evidence that monocytes play a pivotal role in mediating the interface between central and peripheral systems via transduction through the blood brain barrier. The proposed study builds on our pilot work by evaluating association between changes in monocyte transcriptome with changes in clinical phenotype and neuropathology over a 24-month period. Using our banked peripheral blood mononuclear cell (PBMC) and plasma samples on a subset of n=250 responders who have been genotyped (U01 OH011864), we will generate monocyte transcriptome profiles from PBMCs at an average sequencing depth of 150M reads per sample, as well as validated plasma markers of cerebral neuropathology (including pTau181, NfL, Aβ42, Aβ40) at both time points (baseline and 24-month follow up). Among these 250 responders, we also have structural and functional MRI neuroimaging for a subset of responders (n=120) from a separate study (U01 OH011314). In Aim 1, we will determine if changes in monocyte transcriptome (gene and alternative splicing (AS) levels) are associated with changes in clinical phenotype. In Aim 2, we will determine if changes in monocyte transcriptome are associated with changes in each plasma protein. Among the genes and AS associated with NfL, we will further determine if they are associated with cortical thickness by integrating the MRI data. In Aim 3, we will identify genetic variants associated with changes in monocyte transcriptome via eQTL and sQTL analyses. The proposed study will be the first to examine monocyte transcriptome and alternative splicing (AS) in individuals converting to dementia. The in-depth understanding of biological processes underlying the dynamics of monocytes in MCI and how the processes are associated with disease progression can help identify novel blood-based biomarkers for ADRD and intervention strategies that target relevant pathways early in the disease to prevent or slow the progression of neurocognitive disorders.

抽象的 9/11 事件发生十九年后，世贸中心 (WTC) 的大部分响应者表现出精神高度紧张 以及身体健康影响，包括高于预期的轻度认知障碍 (MCI) 负担、 阿尔茨海默病 (AD) 或相关痴呆症 (ADRD) 的早期征兆，因为有可能。 MCI 所表明的神经退行性疾病令人担忧，因此迫切需要了解 疾病的发病机制并确定生物标志物，以便在发生不可逆转的变化之前进行早期干预 我们的试点工作表明，单核细胞亚群的变化最大。 与 MCI 相关的转录组和差异表达 (DE) 基因在通路中富集 这些发现与单核细胞在神经炎症中发挥关键作用的证据一致。 通过血脑屏障的转导介导中枢和外周系统之间的界面。 拟议的研究建立在我们的试点工作的基础上，通过评估单核细胞变化之间的关联 使用我们存储的 24 个月内临床表型和神经病理学变化的转录组。 外周血单核细胞 (PBMC) 和血浆样本，取自 n=250 名应答者的子集，这些应答者患有 经过基因分型（U01 OH011864）后，我们将平均从 PBMC 生成单核细胞转录组图谱 每个样本 150M 读数的测序深度，以及经过验证的脑神经病理学血浆标记物 （包括 pTau181、NfL、Aβ42、Aβ40）在这 250 个时间点（基线和 24 个月随访）。 对于应答者，我们还对来自应答者的子集 (n=120) 进行了结构和功能 MRI 神经影像检查 一项单独的研究（U01 OH011314）在目标 1 中，我们将确定单核细胞转录组（基因和转录组）是否发生变化。 选择性剪接（AS）水平）与临床表型的变化相关。在目标 2 中，我们将确定是否与临床表型的变化相关。 单核细胞转录组的变化与每个血浆蛋白的变化有关。 AS 与 NfL 相关，我们将通过整合 在目标 3 中，我们将通过 eQTL 识别与单核细胞转录组变化相关的遗传变异。 和 sQTL 分析将是第一个检查单核细胞转录组和替代的研究。 转化为痴呆的个体中的剪接（AS） 深入了解生物过程。 MCI 中单核细胞动态的基础以及这些过程如何与疾病进展相关 可以帮助识别 ADRD 的新型血液生物标志物和针对相关的干预策略 疾病的早​​期途径，以预防或减缓神经认知障碍的进展。