Analysis of the domain specific functions of IKK1 and the role of the alternative NFkappaB pathway and IKK1 in germinal center B cells

IKK1 的域特异性功能分析以及替代 NFkappaB 通路和 IKK1 在生发中心 B 细胞中的作用

• 批准号: 193756470
• 负责人: Professorin Dr. Julia Jellusova
• 金额: --
• 依托单位: Sanford Burnham Prebys Medical Discovery Institute
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/193756470?language=en
• 关键词: Analysis; domain; specific; functions; IKK1

The transcription factor NFkappaB plays a central role in the inducible expression of many genes involved in the mechanisms of innate and adaptive immunity. The two dominant signaling pathways which can lead to the activation of NFkappaB are called the classical and the alternative pathway. The alternative NFkappaB pathway is characterised by the IKK1 mediated phosphorylation of p100 which leads to the release of the NFkappaB dimer p52/RelB. IKK1 itself is activated by NIK mediated phosphorylation. Very recently it was shown in the group of Prof.Dr.Rickert that B cells expressing a mutant IKK1 molecule that cannot be phosphorylated by NIK (IKKAA) do not form germinal centers. The goal of the proposed project is to study the mechanism leading to this phenotype. The main objectives are to analyse the NIK-dependent signaling in B cells, determine the biochemical defects in IKKAA B cells, analyze the intrinsic functions of IKK1 in antigen presenting- and plasma- cells. Further, recent studies indicate that IKK1 possesses also NIK- independent, kinase independent or nuclear functions. To gain insight into these aspects of IKK1 function, B cells expressing IKK1 molecules that a) are unable to enter he nucleus (IKK1NLS) b)are kinase inactive (IKK1KM) c)are constitutively active (IKK1EE) will be studied.

转录因子NFkappaB在先天免疫和适应性免疫机制中涉及的许多基因的诱导表达中起核心作用。可导致NFkappaB激活的两种主要信号通路被称为经典通路和替代通路。另一种NFkappaB途径的特点是IKK1介导的p100磷酸化，导致NFkappaB二聚体p52/RelB的释放。IKK1本身被NIK介导的磷酸化激活。最近，在rickert教授博士的研究小组中发现，表达不能被NIK磷酸化的突变IKK1分子（IKKAA）的B细胞不能形成生发中心。该项目的目标是研究导致这种表型的机制。主要目的是分析B细胞中IKK1依赖的信号，确定IKKAA B细胞的生化缺陷，分析IKK1在抗原提呈细胞和浆细胞中的内在功能。此外，最近的研究表明，IKK1还具有不依赖于NIK、激酶或核的功能。为了深入了解IKK1功能的这些方面，将研究表达IKK1分子的B细胞a)无法进入细胞核（IKK1NLS） B)激酶失活（IKK1KM） c)组成活性（IKK1EE）。