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

项目摘要/摘要 阿尔茨海默病(AD)是全球最常见的痴呆症病因。在美国，它是第五大领头羊 65岁以上老人的死因。描述预测未来认知功能减退率的因素 和痴呆症很重要，但还没有完全了解。与疾病进展相关的知识 生物因素将在设计新的治疗策略以减轻其有害影响和 从而防止相关的认知和行为下降。 本R03的基础研究是一项临床转化研究，使用了系统生物学和 生物信息学技术表征失调炎症途径的遗传和细胞背景 在阿尔茨海默病不同阶段影响纵向认知功能衰退的大脑和外周。我们的 临床上轻度认知障碍AD患者的早期研究表明，临床上 炎症分析物的基线水平最能预测认知快速下降的有意义的程度 CCL2.在这项工作中，我们希望通过深入描述背后的遗传驱动因素来扩展这一初步见解 临床阿尔茨海默病的炎性去调节及其发生在周围和中央的细胞背景 神经系统。我们将通过全基因组(rna-seq)表达变化来确认和验证这些变化。 以及来自其他大型国家数据(ADNI，Accelerating Medicines Partnership-AD)的数据和 特征明确的患者脑脊液中免疫细胞的细胞转录。如果假设 和模型得到验证，这项研究的科学见解将有助于确定新的治疗靶点和 个人对未来精确医学干预的有害炎症反应的倾向 阿尔茨海默病中的神经炎症，以防止疾病进展和认知能力下降。如果假设被发现是 不是这样的，这项研究的结果仍然代表着我们对变异性的认识有了显著的进步 面对神经退行性疾病时个体出现神经炎性反应的倾向 病理学。这项研究的结果将对临床以及未来研究的设计和解释都有帮助。 结果。

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.