Elucidating IKK1 function in germinal center B cell differentiation

阐明 IKK1 在生发中心 B 细胞分化中的功能

基本信息

批准号：
8053310
负责人：
ROBERT C RICKERT
金额：
$ 19.1万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8053310
关键词：
Ablation Affinity Alleles Antibody-Producing Cells Antigen-Presenting Cells Apoptosis Area B cell differentiation B-Cell Development B-Lymphocytes Binding Biochemical Biocompatible Materials Catalytic Domain Cell Nucleus Cell physiology Cells Complement Complex Cues DNA Binding Defect Embryo Exploratory/Developmental Grant Generations Goals Humoral Immunities Immunization In Situ In Vitro Individual Infection Inflammatory Lymphoid Tissue Memory B-Lymphocyte Molecular Mus Mutation NF-kappa B Nuclear Nuclear Translocation Pathway interactions Phosphorylation Phosphorylation Site Phosphotransferases Process Property Publishing Reaction Receptors, Tumor Necrosis Factor, Type II Reporting Research Research Personnel Role Signal Transduction Staging Stimulus Structure of germinal center of lymph node T-Lymphocyte TNFRSF5 gene Work animal model development base cell type in vivo insight mouse model mutant p65 prevent public health relevance research study skeletal

项目摘要

DESCRIPTION (provided by applicant): NF-kB signaling is regulated by the IkB kinase complex, consisting of IKK1, IKK2 and NEMO. However, recent studies have shown that IKK1 and IKK2 have largely distinct functions. In the proposed work, we will determine the intrinsic functions of IKK1 in GC B cells. We have recently reported that B cells expressing a mutant IKK1 molecule that cannot be phosphorylated by NIK (IKK1AA) do not form GCs. Herein we will determine the basis for this finding by examining IKK1- dependent functions in the GC via CD40/BAFF-R/TNF-R2 signaling and T cell costimulation. We will also assess activation of the IKK1 pathway in situ using immunohistochemical approaches. To complement these studies, mice will be generated expressing conditional IKK1flox/flox alleles to intercross with inducible B cell-specific Cre-expressing mice, thus allowing us to identify IKK1-dependent B cell functions prior to and during/after the GC reaction. These mice will be intercrossed with mice bearing mutant conditional IKK1 alleles to probe domain-specific functions of IKK1. Together, the proposed studies will provide definitive mechanistic insight into IKK1 function in vivo. PUBLIC HEALTH RELEVANCE: Germinal centers are microenvironments that form in the secondary lymphoid tissues following infection or immunization. It is here where B lymphocytes are selected to be high-affinity memory B cells or antibody-producing cells. Thus, understanding the molecular cues that guide germinal center B cell development is critical to understanding the basis of humoral immunity.

描述（由申请人提供）：NF-KB信号由IKB激酶复合物调节，由IKK1，IKK2和NEMO组成。但是，最近的研究表明，IKK1和IKK2具有很大不同的功能。在拟议的工作中，我们将确定GC B细胞中IKK1的固有功能。我们最近报道说，表达突变体IKK1分子的B细胞不能被NIK（IKK1AA）磷酸化。本文中，我们将通过CD40/BAFF-R/TNF-R2信号传导和T细胞共刺激来检查GC中的IKK1依赖性功能，从而确定这一发现的基础。我们还将使用免疫组织化学方法来评估IKK1途径的激活。为了补充这些研究，将产生小鼠，以表达有条件的IKK1FLOX/FLOX等位基因，以与诱导B细胞特异性CRE表达的小鼠间ro可，从而使我们能够在GC反应之前和期间识别IKK1依赖性B细胞功能。这些小鼠将与轴承有条件IKK1等位基因的小鼠间交叉以探测IKK1的域特异性功能。拟议的研究将共同提供对体内IKK1功能的明确机械洞察力。公共卫生相关性：生发中心是感染或免疫后次要淋巴组织中形成的微环境。在这里，选择B淋巴细胞是高亲和力记忆B细胞或产生抗体的细胞。因此，了解指导生发中心B细胞发育的分子提示对于理解体液免疫的基础至关重要。