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Impact of insulin receptor signaling on T cell function and adaptive immunity

胰岛素受体信号传导对 T 细胞功能和适应性免疫的影响

基本信息

批准号：
199123774
负责人：
Professor Dr. Holger M. Reichardt
金额：
--
依托单位：
Institut für Zelluläre und Molekulare Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/199123774?language=en
关键词：
Impact insulin receptor signaling cell

项目摘要

Type 2 diabetes mellitus (T2DM) is a severe problem of western societies. While angiopathies account for most complications, problems are also caused by the compromised immune system of T2DM patients. Activated T cells express insulin receptors (INSR) and downstream signaling molecules, which is presumably required for an adequate immune response. To investigate the role of the INSR for T cell function we will use inducible knock-down rats allowing for its inactivation after Doxycycline administration. Initially, we will determine whether the function of T helper, cytotoxic T and regulatory T cells is compromised in the absence of the INSR. In the second part, we will investigate the signaling pathways employed by the INSR in T cells and challenge our hypothesis that it may serve to enhance glucose mobilization in concert with CD28. Antigen-specific T cells will be analyzed in two models concerning their migratory behavior, which is a particularly energy-demanding feature of effector cells. Finally, we will generate hematopoietic stem cell chimeras where gene inactivation is limited to the immune system to study the impact of INSR expression on two distinct inflammatory diseases. To this end, we will induce experimental autoimmune encephalomyelitis (EAE) as a typical model for cellular immunity, and allergic airway hypersensitivity (AAH) as an example of a humoral immune response. Collectively, these analyses should provide insight into the role and mechanism of INSR signaling in the immune system and help to better understand the compromised immune status of T2DM patients.

2型糖尿病(T2 DM)是西方社会的一个严重问题。虽然血管病变是大多数并发症的原因，但T2 DM患者的免疫系统受损也会导致问题。激活的T细胞表达胰岛素受体(INSR)和下游信号分子，这可能是充分的免疫反应所必需的。为了研究INSR对T细胞功能的作用，我们将使用可诱导的基因敲除大鼠，允许其在多西环素注射后失活。最初，我们将确定在没有INSR的情况下，T辅助细胞、细胞毒性T细胞和调节性T细胞的功能是否受到损害。在第二部分中，我们将研究INSR在T细胞中所采用的信号通路，并挑战我们的假设，即INSR可能与CD28共同作用于增强葡萄糖动员。抗原特异性T细胞将在两个模型中分析其迁移行为，这是效应细胞的一个特别需要能量的特征。最后，我们将产生造血干细胞嵌合体，其中基因失活仅限于免疫系统，以研究INSR表达对两种不同的炎症性疾病的影响。为此，我们将诱导实验性自身免疫性脑脊髓炎(EAE)作为典型的细胞免疫模型，并将过敏性呼吸道超敏反应(AAH)作为体液免疫反应的例子。总之，这些分析应该有助于深入了解INSR信号在免疫系统中的作用和机制，并有助于更好地了解T2 DM患者的免疫受损状态。