Schizophrenia and autoimmune disorders: the role of microglial cells

精神分裂症和自身免疫性疾病：小胶质细胞的作用

• 批准号: 10458482
• 负责人: Jingchun Chen
• 金额: $ 39.95万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458482
• 关键词: Affect; Animal Model; Applications Grants; Autoimmune Diseases; Autopsy; Bioinformatics; Biological; Biological Markers; Biology; Biotechnology; Blood; Blood specimen; Brain; Caring; Celiac Disease; Cell Line; Cell model; Cell physiology; Cells; Centers of Research Excellence; Chronic; Complex; Data; Data Set; Development; Diagnosis; Disease; Etiology; European; Functional disorder; Gene Expression Profile; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Goals; Grant; Histocompatibility; Human; Immune; Immune system; Incidence; Infection; Inflammation; Inflammatory; Institutes; Insulin-Dependent Diabetes Mellitus; Interleukin-1 beta; Interleukin-6; Lead; Measures; Mediating; Mediator of activation protein; Mental disorders; Meta-Analysis; Microglia; Morphology; Multiple Sclerosis; Mutation; National Institute of Mental Health; Neurobiology; Neurons; Nevada; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pernicious Anemia; Phagocytosis; Phenotype; Population; Process; Psoriasis; Publications; Research; Research Personnel; Research Project Grants; Risk Factors; Role; Schizophrenia; Subgroup; Surface; TNF gene; Techniques; Testing; Tissues; Validation; Withdrawal; brain tissue; career; career development; comorbidity; cost; cytokine; database of Genotypes and Phenotypes; disorder subtype; effective therapy; epidemiology study; experience; genetic architecture; genetic risk factor; genome wide association study; genome-wide; imaging study; interest; molecular marker; monocyte; novel; novel therapeutic intervention; personalized medicine; protein expression; repository; risk variant; schizophrenia risk; severe psychiatric disorder; synergism

ABSTRACT: RESEARCH PROJECT 3  Schizophrenia (SCZ) is a complex psychiatric disorder that presents unique challenges in the study of disease biology. There are no objective biological phenotypes and the etiology is unknown. These lead to tremendous difficulty in diagnosis and treatments. The study of neurobiology underlying this severe psychiatric disorder has been hindered by the lack of access to the tissue of interest – neurons or other cells like microglia (the resident immune cells) from patients' brain. In recent years, several lines of studies have found that SCZ has high co-occurrence with autoimmune disorders (AIDs). Lately, evidence has also highlighted that microglial activation contributes to the risk of SCZ. Several hypotheses have been proposed regarding these studies. One hypothesis is that common genetic alterations or biological pathways are involved in the pathogenesis of both SCZ and AIDs. Another is the microglial activation hypothesis that pro-inflammatory cytokines such as IL- 1β, IL-6 and TNF-α, produced by chronically activated microglia in the brain, are the fundamental mediators for SCZ. However, genetic overlap between SCZ and AIDs at a genome-wide level is largely unknown due to both complex disorders have a complex genetic architecture. In addition, no studies have tested directly in microglia derived from living patients, and the mechanism of microglial activation in the process of SCZ remains unclear. In this application, we hypothesize that common genetic risk factors contribute to a high incidence between SCZ and AIDs, and that microglial activation is a key step in the development of SCZ. Two specific aims are proposed in this study. In Aim 1, we will identify the shared genetic risk factors between SCZ and AIDs using meta-analysis and polygenic analysis. Potential shared pathways between these disorders are also examined. In Aim 2, we will investigate whether the microglial activation enhance the risk of SCZ. We will first establish induced microglia-like cells (iMGCs) from blood monocytes. We will then characterize and validate our iMGC model by morphology and functional study. Finally we will apply the iMGC model to investigate the role of microglia in the development of SCZ. To our knowledge, we will be the first to investigate the common genetic risk factors/pathways between SCZ and AIDs. We will also be the first to investigate the functions of microglia that are directly induced from blood monocytes of SCZ patients. These studies will allow us to pinpoint if, and to what extent, the immune system, including the AIDs risk genes and microglial activation, involve in the development of SCZ. Overall, our proposal has a potential to identify the immune-related risk factors in the etiology of SCZ, which may in turn lead to the discovery of reliable biomarkers and new therapeutic strategies for the care of SCZ patients. This grant will also pave a way for my career development. As I accumulate data and publications, I will be able to apply for R15/R01 grants starting at Years 2-3. My optimal goal is to get an R01 by the end of this grant and establish myself to be an independent investigator.

摘要：研究项目3 精神分裂症（SCZ）是一种复杂的精神病，在研究中提出了独特的挑战 疾病生物学。没有客观的生物学表型，病因尚不清楚。这些导致 诊断和治疗方面的巨大困难。神经生物学的研究是这种严重的精神病学 由于缺乏进入感兴趣的组织的障碍而阻碍了疾病 - 神经元或其他细胞（如小胶质细胞） （居民免疫）来自患者的大脑。近年来，几项研究发现SCZ 与自身免疫性疾病（AIDS）具有很高的同时出现。最近，证据还强调了小胶质 激活有助于SCZ的风险。关于这些研究，已经提出了几种假设。 一种假设是，常见的遗传改变或生物学途径与 SCZ和AIDS。另一个是小胶质激活假说，即促炎性细胞因子（例如IL-） 1β，IL-6和TNF-α是由大脑慢性激活的小胶质细胞产生的，是用于的基本介体 SCZ。然而，由于两者，SCZ和AIDS之间的遗传重叠在基本上水平上是未知的 复杂的疾病具有复杂的遗传结构。此外，没有直接在小胶质细胞中进行研究 源自活着的患者，而在SCZ过程中小胶质激活的机制尚不清楚。 在此应用中，我们假设常见的遗传危险因素有助于 SCZ和AIDS，而小胶质激活是SCZ发展的关键步骤。两个具体目标是 在这项研究中提出。在AIM 1中，我们将使用SCZ和AIDS之间的共同遗传风险因素使用 荟萃分析和多基因分析。还检查了这些疾病之间的潜在共享途径。 在AIM 2中，我们将研究小胶质激活是否会增强SCZ的风险。我们将首先建立 来自血液单核细胞的诱导小胶质细胞样细胞（IMGC）。然后，我们将表征和验证我们的IMGC 形态和功能研究模型。最后，我们将应用IMGC模型调查 SCZ发展中的小胶质细胞。据我们所知，我们将是第一个研究常见遗传的人 SCZ和AIDS之间的风险因素/途径。我们还将是第一个研究小胶质细胞功能的人 直接从SCZ患者的血液单核细胞诱导的。这些研究将使我们能够指出是否，并且 免疫系统在多大程度上，包括艾滋病风险基因和小胶质激活，涉及 SCZ的发展。总体而言，我们的建议有可能确定与免疫相关的危险因素 SCZ的病因，这可能导致发现可靠的生物标志物和新的治疗策略 为了照顾SCZ患者。这笔赠款还将为我的职业发展铺平一种方式。当我累积数据时 和出版物，我将能够从2 - 3年级开始申请R15/R01赠款。我的最佳目标是获得 R01到本赠款结束时，并确定自己是一名独立的调查员。