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: 10469387
• 负责人: DAVID G. STANDAERT
• 金额: $ 41.99万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469387
• 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揭示大脑和身体之间复杂的相互作用 疾病，特别是免疫系统。先天免疫由髓系细胞介导： 源自骨髓的单核细胞、由单核细胞浸润产生的组织巨噬细胞和 分化，以及独立源自胚胎卵黄的大脑常驻小胶质细胞 囊。根据我们来自 P20 探索性资助计划的初步数据，在该项目中，我们的总体目标是 假设是先天免疫细胞在早期就被激活为促炎表型 PD。我们推测阻断这种激活可以防止 PD 进展 可用数据的严格性存在严重差距，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）几乎所有以前的研究 PD 的炎症标志物包括患有多种疾病的异质患者群体 严重程度、持续时间和治疗； 2）人们对性别这一生物学变量缺乏关注； 3）那里 之前没有直接检查早期 PD 中单核细胞群的研究，我们假设这是 极其重要； 4）关于炎症标志物纵向变化的信息很少； 5）有 将大脑和血液炎症标记物与结果联系起来的数据很少。通过 P20 计划，我们 建立了研究早期、从头 PD（该术语的意思是患者）的独特人类受试者队列的能力 尚未接受任何抗 PD 药物治疗的人），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。在目标 1 中，我们 将研究由 60 名新发 PD 患者和 60 名年龄和性别匹配的对照者组成的队列，这些对照者由 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相关 通过对血液单核细胞、血液和脑脊液细胞因子的综合分析来确定早期帕金森病的炎症 趋化因子，以及使用 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，我们将检查炎症基线测量值与 早期新发帕金森病受试者群体的纵向临床结果，特别是认知能力 这些目标与阿拉巴马州尤德尔中心的其他组成部分紧密结合。所有的人类 数据和生物样本取自临床研究核心，并将在项目 2（Benveniste、 重点关注 JAK/STAT 信号）和项目 3（West，重点关注 LRRK2）。总之，这些研究应该 全面了解免疫细胞在帕金森病中的作用，并确定治疗靶点。