Schizophrenia and autoimmune disorders: the role of microglial cells

摘要：研究项目3： 精神分裂症(SCZ)是一种复杂的精神障碍，在精神分裂症的研究中提出了独特的挑战 疾病生物学。目前尚无客观的生物学表型，病因不明。这些导致了 诊断和治疗难度极大。这种严重精神疾病背后的神经生物学研究 由于无法接触到感兴趣的组织-神经元或小胶质细胞等其他细胞，紊乱受到了阻碍 (常驻免疫细胞)来自患者的大脑。近年来，多项研究发现，SCZ 与自身免疫性疾病(艾滋病)有很高的同现性。最近，证据也突显了小胶质细胞 激活增加了SCZ的风险。关于这些研究，已经提出了几个假设。 一种假说认为，常见的遗传改变或生物途径参与了该病的发病。 SCZ和艾滋病都有。另一种是小胶质细胞激活假说，如IL-1等促炎细胞因子 1脑内长期激活的小胶质细胞产生的β、IL-6和肿瘤坏死因子-α是 SCZ.然而，SCZ和艾滋病之间在基因组水平上的遗传重叠在很大程度上是未知的，因为两者 复杂的疾病有一个复杂的遗传结构。此外，还没有研究直接对小胶质细胞进行测试。 小胶质细胞来源于活体患者，小胶质细胞在SCZ过程中的激活机制尚不清楚。 在这个应用中，我们假设共同的遗传风险因素导致了 小胶质细胞的激活是SCZ发生发展的关键步骤。两个具体目标是 在本研究中提出。在目标1中，我们将使用以下方法确定SCZ和AIDS之间共同的遗传风险因素 Meta分析和多基因分析。还研究了这些疾病之间潜在的共同途径。 在目标2中，我们将研究小胶质细胞的激活是否会增加SCZ的风险。我们将首先建立 从血单核细胞中诱导小胶质细胞样细胞(IMGC)。然后，我们将对我们的iMGC进行表征和验证 通过形态和功能研究建立模型。最后，我们将应用iMGC模型来研究 小胶质细胞在SCZ发育中的作用。据我们所知，我们将是第一个研究共同基因的人 SCZ与艾滋病之间的危险因素/途径。我们还将第一个研究小胶质细胞的功能。 直接从SCZ患者的血单核细胞诱导而来。这些研究将使我们能够准确地确定 免疫系统，包括艾滋病危险基因和小胶质细胞激活，在多大程度上参与了 SCZ的发展。总体而言，我们的建议有可能确定与免疫相关的风险因素 SCZ的病因学，这反过来可能导致发现可靠的生物标志物和新的治疗策略 用于SCZ患者的护理。这笔助学金也将为我的职业发展铺平道路。当我积累数据的时候 和出版物，我将能够申请R15/R01资助，从2-3年级开始。我的最佳目标是拿到一个 R01在这笔赠款结束时，并确立我自己是一名独立调查员。

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.