Transcriptional Control of Autoimmunity in the Central Nervous System

中枢神经系统自身免疫的转录控制

• 批准号: 8788961
• 负责人: Howard L Weiner
• 金额: $ 111.36万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788961
• 关键词: Animal Model; Animals; Area; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Autoimmunity; CNS autoimmunity; Cells; Central Nervous System Diseases; Chronic; Dendritic Cells; Development; Disease; Drug Targeting; Effector Cell; Experimental Autoimmune Encephalomyelitis; Gene Expression Profiling; Generations; Goals; Human; Immune; Immune Targeting; Immune response; Immune system; Inflammation; Inflammatory; Interferons; Interleukin-10; Investigation; Mediating; Molecular; Multiple Sclerosis; Neuraxis; Pathology; Pathway Analysis; Pathway interactions; Patients; Peripheral; Phase; Play; Population; Program Research Project Grants; Regulation; Regulatory T-Lymphocyte; Relapse; Relapsing-Remitting Multiple Sclerosis; Research Personnel; Role; Services; T-Lymphocyte; Technology; Tissues; Transcriptional Regulation; autoreactive T cell; cytokine; design; digital; immune function; nano-string; programs; public health relevance; stem; targeted treatment; transcription factor; transcriptome sequencing; white matter

DESCRIPTION (provided by applicant): This is a revised PPG application to build a better understanding of T cell mechanisms in autoimmunity that has stemmed from the discovery of critical regulators of both T effector and T regulatory cells. We have discovered that IL-27 and the transcription factor aryl hydrocarbon receptor (AhR) play central roles in immune responses in animals and humans and these pathways impinge on all aspects of immune function, both adaptive and innate and include Tregs, Th17 cells and dendritic cells. Little is known about these new pathways, which appear crucial in CNS inflammation and have direct relevance to diseases such as multiple sclerosis. The primary goal of this program project grant (PPG) is to identify molecular mechanisms of how IL-27 inhibits effector T cells and induces regulatory Tr1 cells with a focus on two transcription factors cMaf and AhR, both of which are induced by IL-27 in responding Tr1 cells. The investigation of the inter-relationship of cytokines and transcription factors in both animal models and MS patients will allow a better basic understanding of immune abnormalities in MS and allow both the development of more specific immunomodulatory therapy and a mechanistic understanding of current therapies being used to treat MS. IFN¿, a widely used first line therapy in MS has been shown to act in part by the induction of IL-27, underscoring the importance of studying this pathway in CNS autoimmunity. This PPG brings together four investigators, each with unique strengths and expertise to investigate this new area. Project 1: (Kuchroo) "Transcriptional regulation of effector and regulatory T cells in EAE; Project 2: (Littman) "Transcriptional network analysis of Tr1 cells." Project 3: (Quintana) "Role of AhR in the control of the innate immune response during the development of EAE." and Project 4: (Weiner) "Role of IL-27 and AhR in the regulation of human effector and regulatory T cells in healthy subjects and MS patients." The revised PPG will establish a Multi-tiered Expression Analysis Core consisting of two components: Project 2 will undertake expression analysis using RNA-seq and ChlP-seq technologies and Core B will undertake multiplex expression analysis using the latest digital Nanostring technology to analyze the expression of transcripts in subsets and rare populations. The core will service all projects. An Administrative Core will coordinate the various administrative aspects of the PPG and a Scientific Advisory Board has been assembled to provide scientific oversight.

描述（由申请人提供）：这是一份修订后的PPG申请，旨在更好地理解自身免疫中的T细胞机制，该机制源于T效应细胞和T调节细胞的关键调节因子的发现。我们已经发现，IL-27和转录因子芳烃受体（AhR）在动物和人类的免疫应答中起着核心作用，这些途径影响免疫功能的各个方面，包括适应性和先天性免疫功能，包括T细胞，Th 17细胞和树突状细胞。对这些新的通路知之甚少，这些通路在CNS炎症中似乎至关重要，并与多发性硬化症等疾病直接相关。 该计划项目资助（PPG）的主要目标是确定IL-27如何抑制效应T细胞并诱导调节性Tr 1细胞的分子机制，重点是两种转录因子cMaf和AhR，这两种转录因子都是由IL-27诱导的。在动物模型和MS患者中细胞因子和转录因子的相互关系的研究将允许更好地基本理解MS中的免疫异常，并允许开发更特异性的免疫调节疗法和对用于治疗MS的当前疗法的机制理解。广泛应用于MS的一线治疗已显示部分通过诱导IL-27起作用，强调了研究CNS自身免疫中该途径的重要性。 该PPG汇集了四名研究人员，每个人都有独特的优势和专业知识来调查这一新领域。项目一：（Kuchroo）“EAE中效应和调节性T细胞的转录调节;项目2：（Littman）“Tr 1细胞的转录网络分析。“项目3：（Quintana）“AhR在EAE发展过程中控制先天免疫反应的作用。和项目4：（Weiner）“IL-27和AhR在健康受试者和MS患者中调节人效应和调节性T细胞中的作用。" 修订后的PPG将建立一个多层表达分析核心，由两个组成部分组成：项目2将使用RNA-seq和ChlP-seq技术进行表达分析，核心B将使用最新的数字Nanostring技术进行多重表达分析，以分析子集和罕见人群中转录本的表达。核心将服务于所有项目。一个行政核心将协调项目规划小组的各个行政方面，一个科学咨询委员会已经成立，以提供科学监督。