A Systems Approach to Targeting Innate Immunity in AD

针对 AD 中先天免疫的系统方法

• 批准号: 10506095
• 负责人: NILUFER ERTEKIN-TANER
• 金额: $ 39.13万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506095
• 关键词: Address; Administrative Supplement; Aging; Alzheimer' s Disease; Alzheimer' s disease therapy; Award; Benign; Biological Markers; Blood; Cells; Data; Data Set; Disease; Disease Outcome; Etiology; Familiarity; Functional disorder; Genetic; Genetic Transcription; Genomics; Goals; Grant; Immune; Immune System Diseases; Immune system; Immunity; Inflammatory; Kidney; Knowledge; Knowledge Portal; Lupus; Molecular; Molecular Profiling; Myelin; Natural Immunity; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Parents; Parkinson Disease; Pathway interactions; Peripheral; Process; Rheumatoid Arthritis; Role; System; Systemic Lupus Erythematosus; Systemic disease; Tissues; Work; comorbidity; comparative; data sharing; experience; genetic variant; genome wide association study; immune activation; insight; member; new therapeutic target; novel; novel therapeutics; programs; targeted biomarker; transcriptome sequencing; transcriptomics; working group

Summary: This proposal is for an administrative supplement to our existing grant on “A Systems Approach to Targeting Innate Immunity in AD.” We seek support for the harmonized processing and integrated analysis of genomic (GWAS/WES/WGS) and transcriptomic (bulk tissue RNAseq and sc/snRNAseq) data from multiple AMP- programs: AMP-AD, AMP-PD, AMP-RA/SLE and AMP-T2D. The overall goal is to provide novel insights into the role of the immune system in Alzheimer’s disease (AD) and to contribute to ongoing efforts aimed at identifying novel therapeutic targets. We have been members of the AMP-AD consortium since 2013 and have an in-depth knowledge of the available datasets hosted within the AD-knowledge portal. We have generated and contributed data under multiple studies, including Mayo RNAseq, MC-CAA, MCADGS, MCSA and TAUAPPms and have a thorough understanding of the data sharing process. We are/have also been leading and contributing members for multiple working groups within the AMP-AD consortium, affording us familiarity with the data hosted within the portal and the necessary experience in working with big-datasets. A major focus of our prior and ongoing work within AMP-AD is the role of the immune system in AD. In this proposal we aim to expand these efforts to investigate and identify immune signatures that are associated with AD and related disorders and comorbidities including Parkinson’s disease (PD), Type-2-diabetes (T2D), and immune disorders such as rheumatoid arthritis (RA) and lupus (SLE). To accomplish these goals we have three aims that will likewise contribute to the broader aims of the parent U01 and the consortium goal of accelerating the identification of novel therapies for AD. In Aim 1 our goal is to identify genetic variants and transcriptional networks in inflammatory pathways that are shared between as well as distinct for diseases and aging. The central hypothesis of this aim is that there are aspects of the immune system that interact with the aging process and are dysfunctional in disease, some of which will cause broader systemic disease while others may be specific to AD. Defining the aspects of immune dysfunction that contribute to AD more specifically and in the context of aging is expected to address this key knowledge gap. In Aim 2 we plan to discover inflammatory signatures that are shared between as well as tissue- specific. While AD is a neurodegenerative disease, identification of immune changes in peripheral tissues (eg. blood and kidney) that either reflect CNS changes, disease pathophysiology, or systemic immune dysfunction can have implications for furthering understanding of underlying disease etiology and have biomarker potential. In Aim 3 we will expand our analysis to determine inflammatory cell-subtype proportion and cell-specific molecular signature perturbations in disease and aging. While bulk tissue studies have provided key insights into disease such as immune activation and myelin depletion, they largely reflect gross changes within the tissue. Single cell studies are needed to evaluate molecular changes at the cellular level. We expect that comparative analysis of immune genetic and transcriptomic signatures across multiple immunity-involved diseases, tissues and cells will provide knowledge about which aspects of the immune system are benign and which may be targeted with greater effect on disease outcomes.

概括： 该提案是对我们现有的“目标定位系统方法”赠款的行政补充 AD 中的先天免疫。”我们寻求对基因组的协调处理和综合分析的支持 来自多个 AMP 的 (GWAS/WES/WGS) 和转录组（大量组织 RNAseq 和 sc/snRNAseq）数据 计划：AMP-AD、AMP-PD、AMP-RA/SLE 和 AMP-T2D。总体目标是提供新的见解 免疫系统在阿尔茨海默病 (AD) 中的作用，并为旨在识别免疫系统的持续努力做出贡献 新的治疗靶点。自 2013 年以来，我们一直是 AMP-AD 联盟的成员，并拥有深入的了解 AD 知识门户中托管的可用数据集的知识。我们已经产生并贡献了 多项研究的数据，包括 Mayo RNAseq、MC-CAA、MCADGS、MCSA 和 TAUAPPms，并且具有 全面了解数据共享过程。我们现在/也一直是领导和贡献的成员 对于 AMP-AD 联盟内的多个工作组，让我们熟悉内部托管的数据 门户网站以及使用大数据集的必要经验。我们之前和正在进行的一个主要重点 AMP-AD 中的作用是免疫系统在 AD 中的作用。在本提案中，我们的目标是将这些努力扩大到 研究并识别与 AD 及相关疾病和合并症相关的免疫特征 包括帕金森病 (PD)、2 型糖尿病 (T2D) 和类风湿性关节炎等免疫性疾病 （RA）和狼疮（SLE）。为了实现这些目标，我们制定了三个目标，这三个目标同样将有助于更广泛的目标 母公司 U01 的目标和联盟的目标是加速识别 AD 的新疗法。在 目标 1 我们的目标是识别炎症途径中的遗传变异和转录网络 疾病和衰老之间既有共同性，又有不同性。该目标的中心假设是 免疫系统的某些方面与衰老过程相互作用并且在疾病中功能失调，其中一些 这将导致更广泛的全身性疾病，而另一些则可能是 AD 所特有的。定义免疫的各个方面 更具体地说，在衰老的背景下导致 AD 的功能障碍有望解决这一关键问题 知识差距。在目标 2 中，我们计划发现组织之间共享的炎症特征—— 具体的。虽然 AD 是一种神经退行性疾病，但识别周围组织的免疫变化（例如， 血液和肾脏）反映中枢神经系统变化、疾病​​病理生理学或全身免疫功能障碍 可以对进一步了解潜在疾病病因学产生影响，并具有生物标志物潜力。 在目标 3 中，我们将扩展分析以确定炎症细胞亚型比例和细胞特异性 疾病和衰老中的分子特征扰动。虽然大块组织研究提供了重要的见解 免疫激活和髓磷脂耗竭等疾病，它们在很大程度上反映了组织内的总体变化。 需要单细胞研究来评估细胞水平的分子变化。我们预计，比较 分析多种免疫相关疾病、组织的免疫遗传和转录组特征 细胞将提供关于免疫系统的哪些方面是良性的以及哪些方面可能是良性的知识 有针对性地对疾病结果产生更大的影响。