A Systems Approach to Targeting Innate Immunity in AD

总结： 这项建议是对我们现有的"系统性目标选择方法"补助金的行政补充 先天免疫力在AD中。"我们寻求对基因组的协调处理和综合分析的支持， (GWAS/WES/WGS）和转录组学（大量组织RNAseq和sc/snRNAseq）数据。 AMP-AD、AMP-PD、AMP-RA/SLE和AMP-T2D。总的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，并为正在进行的旨在确定 新的治疗靶点。自2013年以来，我们一直是AMP-AD联盟的成员， AD知识门户中托管的可用数据集的知识。我们创造并贡献了 多项研究的数据，包括马约RNAseq、MC-CAA、MCADGS、MCSA和TAUAPPms， 充分了解数据共享过程。我们也是/一直是领导和贡献成员 为AMP-AD联盟内的多个工作组提供了信息，使我们熟悉了 门户网站和使用大型数据集的必要经验。我们先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，我们的目标是扩大这些努力， 研究和鉴定与AD和相关疾病和合并症相关的免疫特征 包括帕金森氏病（PD）、2型糖尿病（T2D）和免疫疾病如类风湿性关节炎 (RA)狼疮（SLE）。为了实现这些目标，我们有三个目标，同样有助于更广泛的 母公司U01的目标和联盟加速识别AD新疗法的目标。在 目的1我们的目标是确定炎症通路中的遗传变异和转录网络， 在疾病和衰老之间共享，也不同。这一目标的核心假设是， 免疫系统与衰老过程相互作用，在疾病中功能失调， 其将引起更广泛的全身性疾病，而其他可能是AD特异性的。定义免疫方面 更具体地说，在衰老的背景下，有助于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，我们计划发现在组织之间共享的炎症特征- 特定.虽然AD是一种神经退行性疾病，但外周组织（例如， 血液和肾脏），反映CNS变化、疾病病理生理学或全身免疫功能障碍 可能对进一步了解潜在疾病病因有意义，并具有生物标志物的潜力。 在目标3中，我们将扩大我们的分析，以确定炎症细胞亚型的比例和细胞特异性 疾病和衰老中的分子特征扰动。虽然大量组织研究提供了关键的见解， 在疾病如免疫激活和髓磷脂耗竭的情况下，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。我们希望，比较 跨多种免疫相关疾病、组织和/或组织的免疫遗传学和转录组学特征分析 细胞将提供有关免疫系统哪些方面是良性的，哪些方面可能是良性的， 对疾病结果产生更大影响的目标。

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.