Project 1: Role of Innate Immune Cells in Human Parkinson Disease

项目1：先天免疫细胞在人类帕金森病中的作用

• 批准号: 9976623
• 负责人: DAVID G. STANDAERT
• 金额: $ 34.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976623
• 关键词: Address; Advisory Committees; Affect; Age; Alabama; Attention; Automobile Driving; Autopsy; Biological; Blood; Bone Marrow; Brain; Brain imaging; Cells; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Data; Clinical Research; Cognition; Cognitive; Complex; Cross-Sectional Studies; Data; Disease; Disease Progression; Disease susceptibility; Embryo; Encephalitis; Flow Cytometry; Future; Genes; Genetic study; Grant; Human; Immune; Immune signaling; Immune system; Individual; Infiltration; Inflammation; Inflammatory; Knowledge; LRRK2 gene; Ligands; Light; Link; Measures; Mediating; Methods; Microglia; Myelogenous; Natural Immunity; Neurobehavioral Manifestations; Outcome; Parkinson Disease; Pathway interactions; Patients; Peripheral; Pharmacotherapy; Phase; Phenotype; Population; Positron-Emission Tomography; Role; Serum; Severity of illness; Signal Transduction; Therapeutic Trials; Time; Tissues; Yolk Sac; adaptive immunity; base; chemokine; cohort; comorbidity; cytokine; design; follow-up; human data; human subject; imaging study; immune activation; immunoregulation; inflammatory marker; insight; macrophage; monocyte; non-motor symptom; potential biomarker; programs; recruit; sex; targeted treatment; transcriptome sequencing

Project Summary: Project 1 Although Parkinson disease (PD) is conventionally thought to be a condition primarily affecting the brain, recent studies have begun to shed light on the complex interactions between the brain and body involved in the disease, particularly the immune system. Innate immunity is mediated by cells of myeloid lineage: monocytes derived from bone marrow, tissue macrophages which arise from monocyte infiltration and differentiation, and the resident microglia of the brain which are independently derived from the embryonic yolk sac. Based on our preliminary data from the P20 Exploratory Grant Program, in this project our overarching hypothesis is that innate immune cells are activated towards a pro-inflammatory phenotype early in PD. We theorize that blocking this activation will protect from PD progression There are critical gaps in rigor of the available data which hinder the design and execution of future therapeutic trials of immunomodulation. These gaps include: 1) nearly all previous studies of inflammatory markers in PD have included heterogeneous groups of patients with a broad range of disease severity, durations and treatments; 2) there has been a lack of attention to sex as a biological variable; 3) there are no previous studies which directly examine monocytes populations in early PD, which we postulate to be critically important; 4) there is little information on longitudinal change in inflammatory markers; and 5) there is little data connecting brain and blood inflammatory markers to outcomes. Through the P20 program, we have established the ability to study a unique human subject cohort of early, de novo PD (a term meaning patients who have not yet received any anti-PD drug therapy) which will allow us to address these critical issues. Here we propose three aims which will directly address these critical knowledge gaps. In Aim 1, we will study a cohort of 60 patients with de novo PD and 60 age- and sex-matched controls recruited by the clinical core. We will determine whether peripheral immune activation or differentiation is associated with CNS inflammation in early PD through integrated analysis of blood monocytes, blood and CSF cytokines and chemokines, and brain imaging with the TSPO ligand 18F-DPA-714. In Aim 2, we will determine whether there is change over time in monocytes populations assessed by flow cytometry or in blood cytokines and chemokines. In Aim 3, we will examine the relationship between baseline measures of inflammation and longitudinal clinical outcomes, particularly cognition, in this population of early de novo PD subjects These Aims are closely integrated with other components of the Alabama Udall Center. All of the human data and biospecimens are drawn from the Clinical Research Core and will be studied in Project 2 (Benveniste, focused on JAK/STAT signaling) and Project 3 (West, focused on LRRK2). Together, these studies should provide a comprehensive view of the role of immune cells in PD, and identify targets for therapy.

项目概要：项目1 虽然帕金森病（PD）通常被认为是一种主要影响大脑的疾病， 最近的研究已经开始阐明大脑和身体之间的复杂相互作用， 疾病，尤其是免疫系统。先天免疫由髓系细胞介导： 来源于骨髓的单核细胞，来源于单核细胞浸润的组织巨噬细胞， 分化，以及独立来自胚胎卵黄的脑的常驻小胶质细胞 囊根据我们从P20探索性资助计划获得的初步数据，在这个项目中，我们的总体目标是： 一种假说认为先天性免疫细胞被激活朝向促炎表型， 警局我们的理论是，阻断这种激活将防止PD进展 在现有数据的严格性方面存在严重差距，这阻碍了 未来的免疫调节治疗试验。这些差距包括：1）几乎所有以前的研究 PD中的炎性标志物包括患有多种疾病的异质性患者组 严重程度，持续时间和治疗; 2）缺乏对性别作为生物学变量的关注; 3） 以前没有直接检查早期PD中单核细胞群的研究，我们假设 至关重要; 4）关于炎性标志物的纵向变化的信息很少;以及5） 几乎没有数据将大脑和血液炎症标志物与结果联系起来。通过P20计划，我们 建立了研究独特的人类受试者队列的能力，早期，新发PD（一个术语，意思是患者 尚未接受任何抗PD药物治疗的患者），这将使我们能够解决这些关键问题。 在这里，我们提出了三个目标，将直接解决这些关键的知识差距。目标1： 将研究一个由60名原发性PD患者和60名年龄和性别匹配的对照组成的队列， 临床核心我们将确定外周免疫激活或分化是否与中枢神经系统 通过综合分析血液单核细胞、血液和CSF细胞因子， 趋化因子和用TSPO配体18F-DPA-714进行脑成像。在目标2中，我们将确定是否存在 是通过流式细胞术评估的单核细胞群或血液细胞因子随时间的变化， 趋化因子在目标3中，我们将检查炎症的基线测量值与 早期初治PD受试者人群的纵向临床结局，特别是认知 这些目标与亚拉巴马尤德尔中心的其他组成部分紧密结合。所有人类 数据和生物样本取自临床研究核心并将在项目2（Benveniste， 重点是JAK/STAT信号传导）和项目3（West，重点是LRRK 2）。总之，这些研究应该 提供免疫细胞在PD中作用的全面观点，并确定治疗靶点。