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之后的二十年，世界贸易中心（WTC）的响应者显示出较高的认知率 障碍（MCI），这是阿尔茨海默氏病（AD）或与AD相关痴呆（ADRD）的早期迹象。 被视为正常衰老和痴呆之间的中间阶段； 了解该疾病的发病机理并确定MCI转化的因素 痴呆症。 尤其是ADRD。 提供有关其病理生理学的见解。 显示了与MCI相关的转录组的最大变化； 通过通过血液转导的中央和外围系统之间介导中央和外围系统之间的界面的关键作用 脑屏障，尽管如此 单核细胞亚群，可能可以解释变化的变化基因表达和蛋白质 与AD神经病和疾病进展相关。 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 在24个月内，通过SMRNA-SEQ在100个响应中。 单核细胞SNCRNA的变化与临床表型的变化有关； 与脑神经病理学相关的单核细胞亚群中的SNCRNA。 研究，包括探索性目的，以通过整合单核细胞SNCRNA，mRNA来识别多摩变签名 预测临床表型的变化的血浆蛋白将检查该研究。 转化为痴呆的个体中的单核细胞SNCRNA，mRNA和血浆蛋白之间的协同作用。 该研究的结果将会照亮疾病进展中的单核细胞反应 基于血液的新型生物标志物可能会为治疗工作提供信息。