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Asb2 in CD4+ T cell lineage differentiation and its plasticity

Asb2在CD4 T细胞谱系分化及其可塑性中的作用

基本信息

批准号：
8660033
负责人：
Xiao-Hong Sun
金额：
$ 21万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660033
关键词：
Animal Model Ankyrin Repeat Antigens Asthma Autoimmunity Biological Assay Bone Marrow Bone Marrow Transplantation Boxing CD4 Positive T Lymphocytes Cell Differentiation process Cell Lineage Cells ChIP-seq Complex Effector Cell Ensure Equilibrium Evaluation Exhibits F-Box Proteins Funding Genes Genetic Recombination Helper-Inducer T-Lymphocyte Immune System Diseases Immunity In Vitro Infection Inflammatory Bowel Diseases Investigation Knockout Mice Laboratories MADH4 gene Maintenance Measures Mediating Modeling Multiple Sclerosis Mus Notch Signaling Pathway Parasites Pattern Play Process Production Proteins Reaction Regulation Regulatory T-Lymphocyte Role Schistosoma mansoni Serum Signal Transduction T cell differentiation T-Lymphocyte T-Lymphocyte Subsets TCF3 gene Testing Th2 Cells Therapeutic Transplantation Ubiquitin Ubiquitination Viral Work aluminum sulfate base cytokine egg fighting genome wide association study in vivo interest mouse model notch protein promoter protein degradation public health relevance response transcription factor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this R21 application is to explore the role of ankyrin-repeat SOCS-box containing protein 2 (Asb2) in the regulation of CD4 helper T cell differentiation. Our previous studies have shown that the Asb2 gene is transcriptionally activated by Notch signaling and Asb2 mediates Notch-induced protein ubiquitination through bridging the formation of dimeric E3 ubiquitin ligase complexes. Asb2 promotes the degradation a large number of proteins including some related to T helper cell differentiation. Interestingly, genome-wide studies have revealed that Asb2 is highly expressed in Th2 cells and repressed in Treg cells. The interesting pattern of expression suggests a potential role for Asb2 in helper T cell differentiation. We hypothesize: (1) Asb2 is crucial for T2 differentiation and maintenance of Th2 lineage fate; (2) Asb2 favors T effector cell fates while suppressing Treg differentiation and destabilizing Treg identifies. We have already generated mouse models in which gain or loss of Asb2 function can be achieved via Cre- mediated recombination. These animal models will be used to test these hypotheses in two aims. Aim1 will explore the role of Asb2 in Th2 differentiation and the stability of the Th2 fate. We will use Asb2 knockout mice to test if loss of Asb2 impairs Th2 differentiation in vitro or destabilizes the Th2 fate when switched to polarizing conditions for Th1, Th17 or Treg. We will then evaluate the role of Asb2 in Th2 responses in vivo by immunizing wild type and Asb2-/- mice with a parasite antigen, the soluble egg antigen (SEA) from Schistosoma mansoni or with OVA in alum. Th2 cytokine secretion and Th2-dependent Ig production in immunized mice will be measured. Aim2 will explore the role of Asb2 in suppressing Treg differentiation. We will ectopically express Asb2 from the ROSA26 promoter in na¿ve T cells and test if Asb2 can block iTreg differentiation in vitro or if Asb2 potentiates the conversion of Treg cells into Th1, Th2 and Th17 lineages. We will also examine Treg differentiation in vivo in Asb2-expressing mice and assess the ability of Asb2- expressing bone marrow to rescue the immune disorder caused by Foxp3-deficient scurfy bone marrow transplanted into RAG1 deficient hosts. Finding from these studies will provide an initial evaluation concerning the role of Asb2 in T helper cell differentiation and lay the ground work for a full-blown in-depth investigation. This line of investigation examines the regulation of T helper cell differentiation from a unique perspective, namely ubiquitin-mediated degradation of regulators of the differentiation. Fresh ideas will likely emerge from these studies that will be o therapeutic value in the contest of immunity and autoimmunity.

描述（由申请人提供）：该R21申请的总体目标是探索含有蛋白2 （Asb2）的anchor -repeat SOCS-box在调节CD4辅助性T细胞分化中的作用。我们之前的研究表明，Asb2基因被Notch信号激活，Asb2通过桥接形成二聚体E3泛素连接酶复合物介导Notch诱导的蛋白泛素化。Asb2促进大量蛋白质的降解，包括一些与T辅助细胞分化相关的蛋白质。有趣的是，全基因组研究表明，Asb2在Th2细胞中高表达，在Treg细胞中被抑制。这种有趣的表达模式提示Asb2在辅助性T细胞分化中的潜在作用。我们推测：(1)Asb2对T2分化和Th2谱系命运的维持至关重要；(2) Asb2有利于T效应细胞命运，抑制Treg分化，破坏Treg鉴定。我们已经建立了小鼠模型，其中Asb2功能的获得或丧失可以通过Cre介导的重组来实现。这些动物模型将用于测试这些假设，有两个目的。Aim1将探讨Asb2在Th2分化中的作用以及Th2命运的稳定性。我们将使用