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.

项目摘要：项目1 尽管帕金森病（PD）通常被认为是主要影响大脑的疾病，但 最近的研究已经开始阐明大脑与身体之间的复杂相互作用 该疾病，特别是免疫系统。先天免疫是由髓样谱系细胞介导的： 源自骨髓的单核细胞，由单核细胞浸润和 分化和大脑的常驻小胶质细胞是独立衍生自胚胎的小胶质细胞 囊。基于我们从P20探索性赠款计划中的初步数据，在此项目中，我们的总体 假设是，先天免疫细胞在早期的促炎表型中被激活 PD。我们认为阻止这种激活将防止PD进展 可用数据严格存在严重的差距，这阻碍了设计和执行 免疫调节的未来治疗试验。这些差距包括：1）几乎所有先前的研究 PD中的炎症标记包括多种疾病的异质组 严重性，持续时间和治疗； 2）缺乏对性作为生物学变量的关注； 3）那里 先前没有研究直接检查早期PD中的单核细胞种群的研究，我们认为这是 至关重要； 4）关于炎症标记纵向变化的信息很少； 5）有 很少有将大脑和血液炎症标记与结果联系起来的数据。通过P20程序，我们有 建立了研究早期，从头pd的独特人类主体队列的能力（术语意味着患者 尚未接受任何抗PD药物疗法的人）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，这些目标将直接解决这些关键的知识差距。在AIM 1中，我们 将研究由60例从头pd的患者组成的队列以及60名年龄和性别匹配的对照组 临床核心。我们将确定周围免疫激活或分化是否与CN相关 通过血液单核细胞，血液和CSF细胞因子和CSF细胞因子的综合分析，早期PD的炎症以及 TSPO配体18F-DPA-714的趋化因子和大脑成像。在AIM 2中，我们将确定是否在那里 通过流式细胞仪或血细胞因子和血细胞因子评估的单核细胞种群中的变化是随着时间的变化 趋化因子。在AIM 3中，我们将研究炎症基线测量与 纵向临床结果，尤其是认知，在从头开始的人群中 这些目标与阿拉巴马州乌德尔中心的其他组件紧密集成。全人 数据和生物测量来自临床研究核心，并将在项目2中进行研究（Benveniste， 专注于JAK/STAT信号传导）和项目3（West，专注于LRRK2）。这些研究应该在一起 对免疫细胞在PD中的作用提供了全面的看法，并确定治疗靶标。