权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Developing a clinical and research framework for evaluating inflammation pathway dysregulation in Alzheimer's disease

开发评估阿尔茨海默病炎症途径失调的临床和研究框架

基本信息

批准号：
10323668
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：
2021-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323668
关键词：
Accounting Acute Address Age Age-Years Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer’s disease biomarker Animal Model Autopsy Behavioral Bioinformatics Biological Factors Biological Markers Brain CCL2 gene Cause of Death Cerebrospinal Fluid Clinical Clinical Research Clinical dementia rating scale Cognitive Data Data Analyses Data Set Databases Dementia Diagnostic Disease Disease Progression Drug Targeting Education Foundations Future Gene Targeting Genes Genetic Genetic Polymorphism Genetic Transcription Goals Health Heterogeneity Human Impaired cognition Inflammation Inflammatory Inflammatory Response Intervention Knowledge Longitudinal cohort Magnetic Resonance Imaging Medicine Modeling Molecular Mutation Nerve Degeneration Neuraxis Neurofibrillary Tangles Outcome Pathologic Pathway interactions Patient Care Patients Persons Play Positron-Emission Tomography Predictive Factor Public Health Regulator Genes Reporting Research Research Personnel Risk Role Senile Plaques Sum TREM2 gene Techniques Testing Therapeutic Up-Regulation Work apolipoprotein E-4 base brain tissue clinical biomarkers clinical care clinically relevant cognitive change cohort cytokine design differential expression gene network gene regulatory network genome wide association study genome-wide improved individual variation inflammatory marker insight interest mild cognitive impairment neuroimaging neuroinflammation neuropathology novel novel therapeutic intervention peripheral blood pre-clinical precision medicine predictive modeling prevent response sex systemic inflammatory response therapeutic target tissue resource transcriptome sequencing 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 bioinformatics and large data analysis techniques to characterize the transcriptional and clinical context of dysregulated inflammatory pathway changes in the brain and periphery that impact longitudinal cognitive decline in different stage of AD. This information will be integrated with prior data on known biomarkers of AD to develop a clinically useful model to focus better targeted patient care. Our earlier work among clinical AD patients at the Mild cognitive impairment stage the disease studies suggest that a clinically meaningful degree of rapid cognitive decline was best predicted by baseline levels of an inflammatory marker, 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 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 (Alzheimer's Disease Neuroimaging Initiative, Accelerating Medicines Partnership-AD and Harvard Brain Tissue Resource Center). These results will be integrated with our knowledge of temporal changes in established AD biomarkers in different clinical stages, to develop a clinically useful framework. The scientific insights and clinical models from this research will help target novel inflammation based therapeutic targets in the most effective stage of AD among clinical patients after taking into account individual variability for deleterious inflammatory responses. This is a much needed step for future precision medicine interventions against neuroinflammation in AD to prevent disease progression.

项目总结/摘要阿尔茨海默病（AD）是全球痴呆症最常见的原因。在美国，它是第五大是65岁以上人群的死亡原因。描述预测未来认知能力下降率的因素和痴呆症是重要的，但尚未被彻底理解。疾病进展相关知识生物学因素在设计新的治疗策略以减轻其有害作用方面将是至关重要的，从而防止相关的认知和行为衰退。 R 03的基础研究是一项使用生物信息学和大数据的临床转化研究用于表征失调的炎症途径的转录和临床背景的分析技术在AD的不同阶段，影响纵向认知下降的大脑和外周的变化。这信息将与已知AD生物标志物的先前数据整合，以开发临床有用的模型，更好地为患者提供有针对性的护理。我们早期在轻度认知障碍的临床AD患者中的工作疾病研究表明，临床上有意义程度的快速认知能力下降是最好的通过炎症标志物CCL 2的基线水平预测。在这项工作中，我们希望扩展这一最初的见解，通过深入表征外周临床AD中炎症失调背后的遗传驱动因素，和中枢神经系统。我们将用全基因组（RNA-seq）来确认和验证这些变化。表达变化和其他大型国家数据（阿尔茨海默病神经影像学倡议，加速药物合作伙伴关系-AD和哈佛脑组织资源中心）。这些结果将与我们对不同临床阶段中已建立的AD生物标志物的时间变化的了解相结合，开发一个临床上有用的框架。这项研究的科学见解和临床模型将有助于在临床患者中AD的最有效阶段中靶向基于炎症的新治疗靶点在考虑了有害炎症反应的个体差异后。这是一个非常需要未来针对AD神经炎症的精准医学干预措施，以防止疾病进展。