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.

项目摘要/摘要阿尔茨海默氏病（AD）是全球痴呆症的最常见原因。在美国，这是第五领先 65岁以上的人死亡原因。划定预测未来认知下降率的因素痴呆症很重要，但尚待彻底理解。与疾病进展有关的知识相关生物学因素对于设计新型的治疗策略至关重要，以减轻其有害影响和从而防止相关的认知和行为下降。 R03基础的研究是一项临床翻译研究，使用生物信息学和大数据分析技术以表征失调炎症途径失调的转录和临床环境影响AD不同阶段纵向认知下降的大脑和周围的变化。这信息将与AD已知生物标志物的先前数据集成，以开发出临床上有用的模型集中精力针对性的患者护理。我们在轻度认知障碍的临床广告患者中的早期工作疾病研究阶段表明，临床上有意义的快速认知下降是最好的通过炎症标记的基线水平CCL2预测。在这项工作中，我们希望扩展这种最初的见解通过深入表征周围临床AD中炎症放松管制背后的遗传驱动因素和中枢神经系统。我们将通过基因组宽（RNA-Seq）确认并验证这些变化表达变化并反对来自其他大型国家数据的数据（阿尔茨海默氏病神经影像学倡议，加速药物合作伙伴关系 - AD和哈佛脑组织资源中心）。这些结果将会与我们了解在不同临床阶段已建立的AD生物标志物的时间变化的了解，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临床患者中最有效的AD最有效阶段的基于新型炎症的新型炎症治疗靶标考虑到有害炎症反应的个人变异性后。这是急需的为了预防疾病进展的AD神经炎症的未来精确医学干预措施。