A Systems Approach to Targeting Innate Immunity in AD

摘要： 这项建议是对我们现有拨款的一项行政补充，该拨款是关于“目标的系统方法” 公元后的先天免疫力。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(大块组织RNAseq和sc/SnRNAseq)数据 方案：AMP-AD、AMP-PD、AMP-RA/SLE和AMP-T2D。总体目标是提供对 免疫系统在阿尔茨海默病(AD)中的作用，并为旨在确定 新的治疗靶点。我们自2013年以来一直是AMP-AD财团的成员，并对 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 在多项研究下的数据，包括Mayo RNAseq，MC-CAA，MCADGS，MCSA和TAUAPPms，并有 对数据共享流程有深入的了解。我们也是/一直是领导和贡献成员 对于AMP-AD联盟内的多个工作组，使我们能够熟悉其中托管的数据 门户网站和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焦点 AMP-AD内的工作是免疫系统在AD中的作用。在这项提案中，我们的目标是将这些努力扩大到 调查并确定与AD及相关疾病和合并症相关的免疫特征 包括帕金森氏症(PD)、2型糖尿病(T2D)和免疫疾病，如类风湿性关节炎 (RA)和狼疮(SLE)。为了实现这些目标，我们有三个目标，这些目标同样将有助于更广泛的 母公司U01的目标和联盟加速确定AD新疗法的目标。在……里面 目标1我们的目标是识别炎症途径中的基因变异和转录网络 在疾病和衰老方面有共同之处，也有不同之处。这一目标的中心假设是有 免疫系统与衰老过程相互作用并在疾病中功能失调的方面，其中一些 这将导致更广泛的系统性疾病，而其他可能是AD特有的。定义免疫的各个方面 在老龄化背景下更具体地导致AD的功能障碍有望解决这一关键问题 知识鸿沟。在目标2中，我们计划发现炎性信号在组织之间以及组织之间共享- 具体的。虽然阿尔茨海默病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)，要么反映中枢神经系统的变化，要么反映疾病的病理生理，要么反映全身免疫功能障碍 可能对进一步了解潜在的疾病病因有意义，并具有生物标志物的潜力。 在目标3中，我们将扩展我们的分析以确定炎性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。虽然大量组织研究提供了对 疾病，如免疫激活和髓鞘耗尽，它们在很大程度上反映了组织内的大体变化。 需要单细胞研究来评估细胞水平上的分子变化。我们预计这一比较 跨多种免疫相关疾病、组织的免疫遗传和转录特征分析 细胞将提供关于免疫系统哪些方面是良性的，哪些可能是良性的知识 有针对性地对疾病结果产生更大的影响。

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.