Regulatory T cell mediated control of colitis by Dkk1
Dkk1 调节性 T 细胞介导的结肠炎控制
基本信息
- 批准号:8583635
- 负责人:
- 金额:$ 23.47万
- 依托单位:
- 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:2013-06-13 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:APC geneAddressAdenomatous Polyposis ColiAffectAutoimmune DiseasesAutoimmunityBiochemicalCD4 Positive T LymphocytesCell Differentiation processCell ProliferationCellsColitisColonComplexCrohn&aposs diseaseDataDisease modelEventFailureHomeostasisImmuneImmune systemIn VitroInflammationInflammatory Bowel DiseasesInflammatory disease of the intestineInterferonsInterleukin-10IntestinesLeadLigandsLymphoid CellMammalian CellMeasuresMediatingMesenteryModelingMusMutant Strains MiceMutationNuclearPathway interactionsPopulationPropertyRecombinantsRegulatory T-LymphocyteRoleSignal PathwaySignal TransductionSignal Transduction PathwaySourceSpleenT cell differentiationT-Cell ActivationT-Cell ProliferationT-LymphocyteTestingTh1 Cellsadaptive immunitycell typeclinical applicationin vivoinhibitor/antagonistintestinal homeostasislymph nodespreventprogramspublic health relevancereceptorreceptor expression
项目摘要
DESCRIPTION (provided by applicant): Accumulation of pathogenic helper CD4 T cells and failure of regulatory T cell (Treg)-mediated suppression are now considered as central to understanding the role of adaptive immunity in autoimmune diseases, including inflammatory bowel disease (IBD). Multiple mechanisms by which Tregs control intestinal inflammation have been suggested but additional mechanisms may exist particularly to maintain homeostasis in the intestinal microenvironment. Our analysis of Wnt ligand expression in distinct lymphoid cell populations revealed that Tregs express the Wnt antagonist Dickkopf1 (Dkk1) significantly higher than other major Wnt ligands, suggesting a potentially important role of Tregs secreting this potent Wnt antagonist. To pursue mechanistic studies we generated a recombinant form of Dkk1 produced in mammalian cells. The findings were notable in that the rDkk1 demonstrated the marked inhibitory effect on naive CD4 T proliferation and stimulation of Treg proliferation. Our preliminary analysis with Tregs from doubleridge mice (Dkk-1 d/d) that express very low level of Dkk-1 showed that indeed these Tregs failed to protect host from colitis by failure to suppress CD4 T cell proliferation. This study utilizing the standard T-cell mediated Inflammatory Bowel Disease (IBD) model allowed us to uncover important properties of Treg that warrant an extensive mechanistic characterization of their function. More importantly, further analysis of CD4 T cell differentiation results showed that rDkk1 inhibited Th1 cell differentiation and markedly elevates IL-10. All of these findings have lead to the hypothesis that Treg-derived Dkk1 is a potent regulator to prevent intestinal inflammation that is critical in IBD. To test thi hypothesis in Aim 1, the mechanism by which Dkk1 inhibits cell proliferation of naive CD4 T cells will be determined in vitro. Naive CD4 T cells lacking the canonical receptor will be utilize to determine whether canonical signaling is required. These cells will also be tested for function in vivo. Finally, we investigate the mechanism to inhibit Th1 polarization and the elevation of IL-10 by Dkk-1. In Aim 2, we will generate Dkk1 deficient Treg utilizing Dkk1 floxed mice. These Dkk1 deficient Treg will be evaluated functionally in the in vivo IBD model. In vitro, the stimulatory effect of Dkk-1 on Tregs will be studied regarding signal transduction pathways that may lead to Treg proliferation. Treg will also be generated that lack the Wnt canonical receptor Lrp5 for assessing the effects of Dkk1 on signaling pathways activating proliferation. We expect these studies to reveal fundamentally important but currently unrecognized properties of Tregs that are essential to understanding autoimmune disease in the intestine but are also generally relevant to autoimmunity. This will likely lead to increased efforts to target Wnt signaling for clinical applications, particularly in Crohn's disease and other autoimmune diseases.
描述(由申请人提供):致病性辅助性CD 4 T细胞的积累和调节性T细胞(Treg)介导的抑制的失败现在被认为是理解适应性免疫在自身免疫性疾病(包括炎症性肠病(IBD))中的作用的核心。已经提出了多种机制,通过这些机制,TdR控制肠道炎症,但可能存在其他机制,特别是维持肠道微环境的稳态。我们对不同淋巴细胞群中Wnt配体表达的分析显示,Tcnt表达的Wnt拮抗剂Dickkopf 1(Dkk 1)显著高于其他主要Wnt配体,表明Tcnt分泌这种有效的Wnt拮抗剂的潜在重要作用。为了进行机制研究,我们产生了在哺乳动物细胞中产生的Dkk 1的重组形式。值得注意的是,rDkk 1对幼稚CD 4 T细胞增殖和Treg增殖的刺激表现出显著的抑制作用。我们对来自表达非常低水平的Dkk-1的doubleridge小鼠(Dkk-1d/d)的TdR的初步分析表明,这些TdR确实不能通过抑制CD 4 T细胞增殖来保护宿主免受结肠炎。这项利用标准T细胞介导的炎症性肠病(IBD)模型的研究使我们能够揭示Treg的重要特性,这些特性保证了其功能的广泛机制表征。更重要的是,进一步分析CD 4 T细胞分化结果显示,rDkk 1抑制Th 1细胞分化并显著升高IL-10。所有这些发现都导致了一种假设,即Treg衍生的Dkk 1是一种有效的调节剂,可以预防IBD中至关重要的肠道炎症。 为了检验目的1中的这一假设,将在体外确定Dkk 1抑制初始CD 4 T细胞的细胞增殖的机制。将利用缺乏典型受体的初始CD 4 T细胞来确定是否需要典型信号传导。还将测试这些细胞的体内功能。最后,我们研究了Dkk-1抑制Th 1极化和升高IL-10的机制。在目标2中,我们将利用Dkk 1 floxed小鼠产生Dkk 1缺陷型Treg。这些Dkk 1缺陷型Treg将在体内IBD模型中进行功能评价。在体外,将研究Dkk-1对Treg增殖的信号转导途径的刺激作用。还将产生缺乏Wnt典型受体Lrp 5的Treg,用于评估Dkk 1对激活增殖的信号传导途径的影响。我们希望这些研究能够揭示Tclase的重要但目前尚未被认识的特性,这些特性对于理解肠道自身免疫性疾病至关重要,但通常也与自身免疫相关。这可能会导致更多的努力,以靶向Wnt信号的临床应用,特别是在克罗恩病和其他自身免疫性疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Alfred LM Bothwell其他文献
Alfred LM Bothwell的其他文献
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{{ truncateString('Alfred LM Bothwell', 18)}}的其他基金
Thrombocyte Regulation of Anti-Parasite Immunity
抗寄生虫免疫的血小板调节
- 批准号:
10560466 - 财政年份:2018
- 资助金额:
$ 23.47万 - 项目类别:
Thrombocyte Regulation of Anti-Parasite Immunity
抗寄生虫免疫的血小板调节
- 批准号:
10056191 - 财政年份:2018
- 资助金额:
$ 23.47万 - 项目类别:
Thrombocyte Regulation of Anti-Parasite Immunity
抗寄生虫免疫的血小板调节
- 批准号:
10290880 - 财政年份:2018
- 资助金额:
$ 23.47万 - 项目类别:
Regulatory T Cell Control of Intestinal Tumorigenesis
肠道肿瘤发生的调节性 T 细胞控制
- 批准号:
9024465 - 财政年份:2014
- 资助金额:
$ 23.47万 - 项目类别:
Regulatory T Cell Control of Intestinal Tumorigenesis
肠道肿瘤发生的调节性 T 细胞控制
- 批准号:
8632371 - 财政年份:2014
- 资助金额:
$ 23.47万 - 项目类别:
Regulatory T Cell Control of Intestinal Tumorigenesis
肠道肿瘤发生的调节性 T 细胞控制
- 批准号:
9379022 - 财政年份:2014
- 资助金额:
$ 23.47万 - 项目类别:
Regulatory T Cell Control of Intestinal Tumorigenesis
肠道肿瘤发生的调节性 T 细胞控制
- 批准号:
9206553 - 财政年份:2014
- 资助金额:
$ 23.47万 - 项目类别:
Regulatory T cell control of intestinal tumorigenesis
调节性 T 细胞控制肠道肿瘤发生
- 批准号:
8967818 - 财政年份:2014
- 资助金额:
$ 23.47万 - 项目类别:
Regulatory T cell mediated control of colitis by Dkk1
Dkk1 调节性 T 细胞介导的结肠炎控制
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8496111 - 财政年份:2011
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