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.

摘要