Changes in monocyte small noncoding RNAs as a predictor of cognitive decline in mild cognitive impairment and Alzheimer's disease

单核细胞小非编码 RNA 的变化可作为轻度认知障碍和阿尔茨海默病认知能力下降的预测因子

• 批准号: 10646566
• 负责人: Pei-Fen Kuan
• 金额: $ 27.91万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646566
• 关键词: Abeta clearance; Affect; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Apoptosis; Biological; Biological Markers; Biological Process; Blood - brain barrier anatomy; Cause of Death; Cells; Cerebrum; Clinical Data; Cognition; Communication; Correlation Studies; DNA; Data; Dementia; Development; Disease; Disease Progression; Epidemiology; Epigenetic Process; Etiology; Feasibility Studies; Functional disorder; Gene Expression; Gene Proteins; Gene Targeting; General Population; Genetic Transcription; Health; Human; Immune response; Immune system; Impaired cognition; Impairment; Individual; Inflammation; Knowledge; Longitudinal Studies; Machine Learning; Mediating; Metabolism; MicroRNAs; Modification; Molecular; Molecular Profiling; Molecular Target; Nerve Degeneration; Neuropathy; Parietal Lobe; Pathogenesis; Pathologic Processes; Pathway interactions; Peripheral; Plasma Proteins; Play; Process; RNA; Recovery; Regulation; Reporting; Research; Research Design; Research Personnel; Role; Sampling; Survivors; Symptoms; Synaptic plasticity; System; Tauopathies; Temporal Lobe; Terrorism; Time; Trauma; United States; Untranslated RNA; Work; biobank; blood-based biomarker; cerebral atrophy; clinical phenotype; cognitive function; cohort; cost effective; deep sequencing; early detection biomarkers; epigenetic regulation; experience; follow-up; frontal lobe; gene environment interaction; genome-wide; immunoreaction; insight; mild cognitive impairment; monocyte; multiple omics; neuroinflammation; neuronal growth; neuropathology; neurotoxic; normal aging; novel; potential biomarker; programs; protein biomarkers; response; single-cell RNA sequencing; symptom treatment; synergism; transcriptome; transcriptomics

ABSTRACT Twenty years after 9/11, the World Trade Center (WTC) responders show elevated rates mild cognitive impairment (MCI), an early sign of Alzheimer’s disease (AD) or AD-related dementia (ADRD). MCI is often regarded as an intermediate stage between normal aging and dementia; thus it provides a window of opportunity to understand the pathogenesis of the disorder and identify factors that lead to the conversion of MCI to dementia. Epigenetic vulnerability and gene-environment interactions have been implicated in the etiology of ADRD. In particular, small noncoding RNAs (sncRNAs) have been shown to be promising biomarkers and provide insights into its pathophysiology. Preliminary findings further revealed that monocyte subpopulation showed the largest changes in transcriptome associated with MCI; 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. Despite this, there is no study which has investigated the epigenetic regulation by sncRNAs in monocyte subpopulation that may explain how these changes affect downstream gene expression and proteins associated with AD neuropathy and disease progression. This proposal builds on the preliminary findings in monocyte transcriptome and capitalizes on existing biobank and clinical data by evaluating monocyte sncRNA via smRNA-seq in a subset of 100 responders over a 24-month period. The proposed study will determine if changes in monocyte sncRNAs are associated with changes in clinical phenotype; and identify the gene targets of sncRNAs in monocyte subpopulation associated with cerebral neuropathology. To enhance the impact of this study, an exploratory aim is included to identify a multi-omic signature by integrating monocyte sncRNAs, mRNAs and plasma proteins that predicts changes in clinical phenotype. This study would be the first to examine the synergy between monocyte sncRNAs, mRNAs and plasma proteins in individuals converting to dementia. Findings from this study will shed light on regulation of monocyte responses in disease progression, help identify novel blood-based biomarkers that may inform treatment efforts.

抽象的 9/11 事件二十年后，世界贸易中心 (WTC) 的响应者表现出轻度认知障碍率升高 损伤 (MCI)，通常是阿尔茨海默病 (AD) 或 AD 相关痴呆 (ADRD) 的早期症状。 被认为是正常衰老和痴呆之间的中间阶段；因此它提供了一个机会之窗； 了解该疾病的发病机制并确定导致 MCI 转化为 痴呆症的病因学涉及表观遗传脆弱性和基因-环境相互作用。 特别是，小非编码 RNA (sncRNA) 已被证明是有前途的生物标志物和 初步研究结果进一步揭示了单核细胞亚群。 显示与 MCI 相关的转录组变化最大；这与单核细胞发挥作用的证据一致。 通过血液转导在介导中枢和外周系统之间的界面中发挥关键作用 尽管如此，尚无研究调查 sncRNA 对脑屏障的表观遗传调控。 单核细胞亚群可以解释这些变化如何影响下游基因表达和蛋白质 与 AD 神经病变和疾病进展相关的这一提议建立在初步发现的基础上。 单核细胞转录组，并通过评估单核细胞 sncRNA 来利用现有的生物库和临床数据 拟议的研究将在 24 个月内通过 smRNA-seq 对 100 名应答者进行研究，以确定是否存在这种情况。 单核细胞 sncRNA 的变化与临床表型的变化相关，并确定基因靶标； 与脑神经病理学相关的单核细胞亚群中 sncRNA 的影响。 研究的探索性目标是通过整合单核细胞 sncRNA、mRNA 来识别多组学特征 这项研究将是第一个检查临床表型变化的血浆蛋白。 转化为痴呆的个体中单核细胞 sncRNA、mRNA 和血浆蛋白之间的协同作用。 这项研究的结果将揭示疾病进展中单核细胞反应的调节，帮助识别 可以为治疗工作提供信息的新型血液生物标志物。