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: 10312349
• 负责人: SEAN CLOUSTON
• 金额: $ 49.83万
• 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/10312349
• 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之后的十九年，世界贸易中心（WTC）响应者比例很高，表明心理升高 和身体健康效应，其中包括高度认知障碍（MCI）的预期燃烧高于预期的效果（MCI） 阿尔茨海默氏病（AD）或相关痴呆症（ADRD）的早期迹象。因为潜力 MCI指示的神经退行性疾病是有关键的需要了解的 该疾病的发病机理并识别生物标志物以促进早期干预之前 发生大脑。我们的飞行员工作表明，单核细胞亚群显示出最大的变化 与MCI相关的转录组和不同表达的（DE）基因富含途径 与神经炎症有关。这些发现与证据表明单核细胞在 通过通过血脑屏障的转移来介导中央和外围系统之间的界面。 拟议的研究通过评估单核细胞变化之间的关联来建立我们的试点工作 转录组随临床表型和神经病理学的变化，在24个月内。使用我们的银行 外周血单核细胞（PBMC）和血浆样品，该子集的n = 250个响应者 是基因分型（U01 OH011864），我们将平均从PBMC生成单核细胞转录组曲线 每个样品的测序深度读取150m，以及经过验证的脑神经病理的等离子体标记 （包括PTAU181，NFL，Aβ42，Aβ40）在两个时间点（基线和24个月的随访）。在这250个 响应者，我们还具有一部分响应者（n = 120）的结构和功能性MRI神经成像 另一项研究（U01 OH011314）。在AIM 1中，我们将确定单核细胞转录组的变化（基因和 替代剪接（AS）水平与临床表型的变化有关。在AIM 2中，我们将确定是否 单核细胞转录组的变化与每种血浆蛋白的变化有关。在基因和 与NFL相关，我们将进一步确定它们是否与皮质厚度相关联 MRI数据。在AIM 3中，我们将通过EQTL确定与单核细胞转录组变化相关的遗传变异 和SQTL分析。拟议的研究将是第一个检查单核细胞转录组和替代方案的研究 转化为痴呆的个体中的剪接（AS）。对生物过程的深入了解 MCI中单核细胞的动力学以及过程与疾病进展如何相关的基础 可以帮助确定针对相关的ADRD和干预策略的新型血液生物标志物 疾病早期的途径，以预防或减缓神经认知障碍的进展。