Systems Biology Approach to Molecular Mechanisms of Human TGFb Induced iTreg Cell Differentiation and the Role of iTreg in Multiple Sclerosis

人 TGFb 诱导 iTreg 细胞分化的分子机制以及 iTreg 在多发性硬化症中的作用的系统生物学方法

• 批准号: 212237242
• 负责人: Professor Dr. Heinz Wiendl
• 金额: --
• 依托单位: Department of Computer Science
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/212237242?language=en
• 关键词: Systems; Biology; Approach; Molecular; Mechanisms

Regulation of the immune response is central for human health. T helper (Th) cell subsets orchestrate the adaptive arm of the immune system and their pathological imbalances result in chronic inflammatory and autoimmune diseases. Effector cell functions are suppressed by natural or induced T regulatory cells (Treg and iTreg, respectively). One key assumption for the development of autoimmunity is a dysregulation in the functional capacity and/or development of regulatory immune cell populations. Therefore, understanding the gene regulatory pathways controlling T‐cell differentiation into functionally distinct subsets will be crucial to understand the pathogenesis of immune‐mediated diseases and to develop and understand better immunomodulatory therapies. We propose to to study the effects of TGFb 2(6) during induction of iTreg from naive human CD4+ T cells. We will study whether TGFb mediated induction of Tregs is dysfunctional and what molecular targets might underly this in Multiple sclerosis, a prototypic chronic autoimmune inflammatory disorder, where balance of peripheral immune regulation is considered key to understanding of pathogenesis and early treatment. Our objectives are: 1) To study transcriptional and epigenetic regulation of Th cell differentiation in TGFb induced Treg cells. 2) To develop integrative and dynamic models of key differentiation mechanisms, assess effects of disease related mutations, and identify points of intervention to modulate differentiation response. 3) To investigate the role of new Th cell regulators in human inflammatory disease paradigms (e.g. Multiple sclerosis) and in vivo models (humanized mice). Cutting edge technologies and carefully selected valuable patient samples and records will be exploited to address the questions. Our results are expected to reveal the key regulatory mechanisms of human immune response and pathology and potentially new opportunities for its modulation.

调节免疫反应对人类健康至关重要。辅助性T细胞（Th）亚群协调免疫系统的适应性臂，其病理失衡导致慢性炎症和自身免疫性疾病。效应细胞功能被天然或诱导的T调节细胞（分别为Treg和iTreg）抑制。自身免疫发展的一个关键假设是调节免疫细胞群的功能能力和/或发育失调。因此，了解控制T细胞分化为功能不同亚群的基因调控途径对于理解免疫介导疾病的发病机制以及开发和理解更好的免疫调节疗法至关重要。我们拟研究TGFb 2(6)在诱导人CD4+ T细胞iTreg过程中的作用。我们将研究TGFb介导的Tregs诱导是否功能失调，以及在多发性硬化症（一种典型的慢性自身免疫性炎症性疾病）中可能存在的分子靶点，其中外周免疫调节的平衡被认为是理解发病机制和早期治疗的关键。我们的目标是：1)研究TGFb诱导Treg细胞Th细胞分化的转录和表观遗传学调控。2)建立关键分化机制的综合动态模型，评估疾病相关突变的影响，确定调节分化反应的干预点。3)研究新的Th细胞调节因子在人类炎症疾病（如多发性硬化症）和体内模型（人源化小鼠）中的作用。将利用尖端技术和精心挑选的有价值的患者样本和记录来解决这些问题。我们的研究结果有望揭示人类免疫反应和病理的关键调节机制，并为其调节提供潜在的新机会。