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Integrative analysis of multi-omics data to delineate CCL2 associated inflammatory pathways in Alzheimers Disease

多组学数据综合分析以描绘阿尔茨海默病中 CCL2 相关炎症通路

基本信息

批准号：
10369676
负责人：
Gurkan Bebek
金额：
$ 16.1万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369676
关键词：
Accounting Acute Address Affect Age Age-Years Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Anatomy Animal Model Area Automobile Driving Behavioral Bioinformatics Biological Biological Factors Biological Markers Brain CCL2 gene Cause of Death Cells Cerebrospinal Fluid Clinical Clinical dementia rating scale Cognitive Data Databases Dementia Disease Disease Progression Education Flow Cytometry Foundations Future Genes Genetic Genetic Polymorphism Genomics Goals Heterogeneity Human Immune Immune System Diseases Immune system Impaired cognition Individual Inflammation Inflammatory Inflammatory Response Intervention Investigation Knowledge Leukocytes MMP3 gene Mediating Medicine Microglia Modeling Molecular Multiomic Data Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Outcome Outcomes Research Pathology Pathway interactions Patients Peripheral Persons Phenotype Plasma Predictive Factor Public Health Regulator Genes Research Risk Role Stem Cell Factor Sum Surface Antigens Symptoms Systems Biology TNFRSF1B gene TREM2 gene Techniques Validation Work apolipoprotein E-4 cell type cohort cytokine design differential expression gene network gene regulatory network genetic signature genome wide association study genome-wide inflammatory marker insight mild cognitive impairment neuroimaging neuroinflammation new therapeutic target novel therapeutic intervention peripheral blood pre-clinical precision medicine prevent response sex systemic inflammatory response therapeutic protein therapeutic target therapy development transcriptome sequencing transcriptomics translational study

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia worldwide. In the US, it is the fifth leading cause of death in people over 65 years of age. Delineating factors that predict rate of future cognitive decline and dementia are important but are yet to be thoroughly understood. Knowledge of disease progression related biological factors will be critical in designing novel therapeutic strategies to mitigate their deleterious effects and thereby prevent the associated cognitive and behavioral decline. The research at the foundation of this R03 is a clinical translational study that uses systems biology and bioinformatics techniques to characterize the genetic and cellular context of dysregulated inflammatory pathways in the brain and periphery that impact longitudinal cognitive decline in different stage of Alzheimer's disease. Our earlier work among clinical patients at the Mild cognitive impairment stage AD suggests that a clinically meaningful degree of rapid cognitive decline was best predicted by baseline levels of an inflammatory analyte CCL2. In this work we hope to extend this initial insight by characterizing in depth the genetic drivers behind the inflammatory deregulation in clinical AD and the cellular context in which it occurs in the periphery and the central nervous system. We will confirm and validate these changes with genome wide (RNA-seq) expression changes and against data from other large national data (ADNI, Accelerating Medicines Partnership-AD) and by single cell transcriptomics of immune cells in the cerebrospinal fluid among well characterized patients. If the hypothesis and models are validated, scientific insights from this research will help identify novel therapeutic targets and individual propensities for deleterious inflammatory responses for future precision medicine interventions against neuroinflammation in AD to prevent disease progression and cognitive decline. If the hypothesis is found to be not true, the findings from this study will still represent a significant advance in our knowledge of variability in individual propensities to have a neuroinflammatory response in the face of neurodegenerative disease pathology. The results of this will be useful both clinically and in designing and interpreting future research outcomes.

项目总结/文摘