THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE
ICSBP 在粘膜免疫反应中的作用
基本信息
- 批准号:7683157
- 负责人:
- 金额:$ 20.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AgreementAntibodiesAutomobile DrivingBindingCellsChronicColitisColonControlled StudyCrohn&aposs diseaseDendritic CellsDevelopmentDiseaseDisruptionEnvironmentFamilyGene ExpressionGenerationsGenus ColaGerm-FreeGoalsHost DefenseHumanIFN consensus sequence binding proteinIL10 geneImmuneImmune responseImmunologicsIndividualInflammationInflammatoryInflammatory ResponseInflammatory disease of the intestineInterferonsInterleukin-10Interleukin-12Knockout MiceLamina PropriaLigandsMediatingMessenger RNAModelingMolecularMononuclearMucosal Immune ResponsesMucositisMusPathway interactionsPatientsPeptidesPlayProductionProteinsReagentRegulationReportingRoleSignal PathwaySignal TransductionSiteStructureSulfonic AcidsT-LymphocyteTLR4 geneTNF receptor-associated factor 6TRAF6 geneTherapeutic EffectToll-like receptorsTrinitrobenzenesUbiquitinUbiquitinationcytokinein vivomacrophagemicrobialmouse modelmulticatalytic endopeptidase complexpathogenpromotertherapeutic targettranscription factorubiquitin-protein ligase
项目摘要
The IFN consensus sequence binding protein (ICSBP/IRF-8), which belongs to the interferon
regulatory factor family of transcription factors, is essential for a Thl immune response.
ICSBP plays an important role in the host defense against microbial pathogens, but the exact
roles of ICSBP in inflammation and chronic inflammatory diseases are still not clear. IL-10-/-
mice, which develop colitis characterized by increased Thl cytokines, mimic many aspects of
human Crohn's disease (CD). The importance of ICSBP in the development of colitis is shown
by the lack of disease in ICSBP and IL-10 double knockout mice. In addition, ICSBP mRNA
and protein are highly expressed in the colons of IL-10-/- mice with colitis, while expression
of IL-12 and iNOS is significantly compromised in ICSBP/IL-10 double KO mice. In agreement
with these results, patients with CD have significantly higher ICSBP expression than normal
individuals. ICSBP is active in several loci. ICSBP interacts with TRAF6 in the TLR4 pathway,
and binds to ISRE sites in the iNOS and IL-12 p40 promoters, activating the expression of
these genes. In addition, we find that ICSBP is ubiquitinated by the E3 ligase Cbl, resulting in
its degradation by the proteasome. To expore ICSBP as a suitable target for therapy in CD,
this proposal is structured around three aims: 1) We will analyze the regulation of ICSBP
expression in macrophages and dendritic cells activated with various TLR and NOD2 ligands.
In addition, we will define the role of ICSBP in the generation of regulatory T cells. 2) We will
define the function of Cbl in the control of Thl immune immune response and analyze the
role of Cbl in the development of colitis. 3) We will define the therapeutic effects of TLR4 and
ICSBP inhibition by cell-permeable peptide reagent in vivo in murine colitis models. These
studies will advance our understanding the role of ICSBP in the mucosal immune response,
and may identify ICSBP as a new target for therapy in CD.
干扰素共有序列结合蛋白(ICSBP/IRF-8)属于干扰素家族,
转录因子的调节因子家族是Thl免疫应答所必需的。
ICSBP在宿主防御微生物病原体中起着重要作用,但确切的ICSBP是一种特异性的蛋白质。
ICSBP在炎症和慢性炎症性疾病中的作用尚不清楚。IL-10-/-
发生以Th 1细胞因子增加为特征的结肠炎的小鼠,模拟了
人克罗恩病(CD)。显示了ICSBP在结肠炎发展中的重要性
ICSBP和IL-10双敲除小鼠没有患病。此外,ICSBP mRNA
和蛋白在IL-10-/-小鼠结肠炎的结肠中高度表达,
ICSBP/IL-10双敲除小鼠IL-12和iNOS的表达显著降低。一致
根据这些结果,CD患者的ICSBP表达显著高于正常人
个体ICSBP在几个位点都有活性。ICSBP在TLR 4途径中与TRAF 6相互作用,
并与iNOS和IL-12 p40启动子中的ISRE位点结合,激活
这些基因。此外,我们发现ICSBP被E3连接酶Cbl泛素化,导致
它被蛋白酶体降解。探讨ICSBP作为治疗CD的合适靶点,
本建议围绕三个目标展开:1)我们将分析ICSBP的监管
在用各种TLR和NOD 2配体活化的巨噬细胞和树突细胞中表达。
此外,我们将定义ICSBP在调节性T细胞生成中的作用。2)我们将
明确Cbl在Thl免疫应答调控中的作用,分析Cbl在Thl免疫应答调控中的作用,
Cbl在结肠炎发展中的作用。3)我们将确定TLR 4的治疗作用,
小鼠结肠炎模型中细胞渗透性肽试剂的体内ICSBP抑制。这些
研究将促进我们对ICSBP在粘膜免疫应答中的作用的理解,
ICSBP可能成为CD治疗的新靶点。
项目成果
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{{ truncateString('HUABAO XIONG', 18)}}的其他基金
T cell-derived iNOS switches off TH17 cell differentiation in inflammation
T 细胞衍生的 iNOS 在炎症中关闭 TH17 细胞分化
- 批准号:
8474949 - 财政年份:2013
- 资助金额:
$ 20.21万 - 项目类别:
T cell-derived iNOS switches off TH17 cell differentiation in inflammation
T 细胞衍生的 iNOS 在炎症中关闭 TH17 细胞分化
- 批准号:
8722431 - 财政年份:2013
- 资助金额:
$ 20.21万 - 项目类别:
T cell-derived iNOS switches off TH17 cell differentiation in inflammation
T 细胞衍生的 iNOS 在炎症中关闭 TH17 细胞分化
- 批准号:
9116764 - 财政年份:2013
- 资助金额:
$ 20.21万 - 项目类别:
Silencing of Th17 cell differentiation by IRF8 in the development of colitis
IRF8 在结肠炎发展过程中沉默 Th17 细胞分化
- 批准号:
8305224 - 财政年份:2011
- 资助金额:
$ 20.21万 - 项目类别:
THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE
ICSBP 在粘膜免疫反应中的作用
- 批准号:
7484982 - 财政年份:2007
- 资助金额:
$ 20.21万 - 项目类别:
THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE
ICSBP 在粘膜免疫反应中的作用
- 批准号:
7141824 - 财政年份:2006
- 资助金额:
$ 20.21万 - 项目类别:
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