Ubiquitylation and the Regulation of Immune Homeostasis

泛素化与免疫稳态的调节

基本信息

批准号：
8728194
负责人：
Robert Cohen
金额：
$ 48.39万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728194
关键词：
A20 protein Anti-Inflammatory Agents Anti-inflammatory Antigens Binding Biochemical Biochemistry C-terminal CD11 Antigens Cell physiology Cells Cellular biology Cleaved cell Cysteine Dendritic Cells Disease Enzymes Exhibits Gene Targeting Genes Goals Homeostasis ITGAX gene Immune Immune response In Vitro Inflammatory Knock-in Mouse Laboratories Ligands Link LoxP-flanked allele Mediating Mouse Strains Mus Mutation N-terminal Natural Immunity Physiological Play Polyubiquitin Proteins Public Health Reagent Receptor Signaling Recruitment Activity Regulation Role Signal Pathway Signal Transduction Signaling Protein Specificity TNF gene TRAF6 gene Toll-like receptors Transgenic Mice Ubiquitin Ubiquitination Work Zinc Fingers in vivo novel peripheral tolerance protein protein interaction response therapy development ubiquitin isopeptidase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are innate immune cells that regulate both immune homeostasis as well as antigen driven immune responses. The functions of DCs are highly regulated by signals initiated by Toll-like receptors (TLRs). Consequently, intracellular molecules that regulate TLR signaling pathways are pivotal for regulating host immune responses. We have recently found that A20 is a ubiquitin modifying enzyme that restricts toll-like receptor (TLR) induced signals. We are studying the roles of A20 expression in DCs in regulating immune homeostasis and responses. To accomplish this, we have generated two strains of gene targeted mice: one that disrupts the A20 gene in all cells and one in which a "floxed" allele of A20 has been targeted to the endogenous A20 locus. We have interbred the "floxed" mice with a novel strain of CD11-Cre transgenic mouse line that expresses Cre enzyme with high selectivity and specificity in DCs. These compound A20flox/flox CD11c-Cre mice will thus provide us with a very powerful and novel reagent for studying the role of A20 expression in DCs in regulating immune homeostasis and immune responses. We propose to use these A20flox/flox CD11-cre compound mice, as well as cells derived from both strains of mice, to determine how A20 expression in DCs regulates their responses to TLR ligands in vitro and in vivo. The first aim will focus upon understanding the cell biology and biochemistry underlying A20's roles in regulating TLR signaling in DCs, and will elucidate the cell-autonomous functions of DCs that are regulated by A20. The second aim will utilize A20flox/flox CD11c-Cre mice to determine how A20 expression in DCs regulates their homeostasis and activation in vivo. This second aim will also interrogate how A20 expression in DCs regulates peripheral tolerance and immune responses.

描述（由申请人提供）：树突状细胞（DC）是天生的免疫细胞，可调节免疫稳态以及抗原驱动的免疫反应。 DC的功能由Toll样受体（TLR）发起的信号高度调节。因此，调节TLR信号通路的细胞内分子是调节宿主免疫反应的关键。我们最近发现，A20是一种泛素修饰酶，限制了类似Toll样受体（TLR）诱导的信号。我们正在研究A20在DC中表达在调节免疫稳态和反应中的作用。为此，我们产生了两种基因靶向小鼠的菌株：一种破坏所有细胞中A20基因的菌株，一个A20的A20等位基因已针对内源性A20基因座。我们已经将“ Floxed”小鼠与新型CD11-CRE转基因小鼠系的新菌株交织在一起，该菌株在DC中表达具有高选择性和特异性的CRE酶。因此，这些化合物A20Flox/Flox CD11C-CRE小鼠将为我们提供一种非常有力和新颖的试剂，用于研究A20在DC中的作用在调节免疫稳态和免疫反应中的作用。我们建议使用这些A20Flox/Flox CD11-CRE化合物以及源自这两种小鼠菌株的细胞来确定DC中的A20表达如何调节其对体外和体内TLR配体的反应。第一个目标将集中在理解A20在调节DC中的TLR信号中的作用的细胞生物学和生物化学，并将阐明由A20调节的DC的细胞自主功能。第二个目标将利用A20Flox/Flox CD11C-CRE小鼠来确定DC中的A20表达如何调节其体内的稳态和激活。第二个目标还将询问DC中的A20表达如何调节外围耐受性和免疫反应。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development.

DOI：
10.1038/nature07575
发表时间：
2009-02-12
期刊：
NATURE
影响因子：
64.8
作者：
Oshima, Shigeru;Turer, Emre E.;Callahan, Joseph A.;Chai, Sophia;Advincula, Rommel;Barrera, Julio;Shifrin, Nataliya;Lee, Bettina;Yen, Benjamin;Woo, Tammy;Malynn, Barbara A.;Ma, Averil
通讯作者：
Ma, Averil

The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity.

DOI：
10.1016/j.immuni.2010.07.017
发表时间：
2010-08-27
期刊：
Immunity
影响因子：
32.4
作者：
Tavares RM;Turer EE;Liu CL;Advincula R;Scapini P;Rhee L;Barrera J;Lowell CA;Utz PJ;Malynn BA;Ma A
通讯作者：
Ma A

From trash collectors to guardians of cell signaling and immune homeostasis.