Control of dysfunctional Tregs
控制功能失调的 Tregs
基本信息
- 批准号:10552603
- 负责人:
- 金额:$ 48.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-02-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAdultAgeAllograftingApoptosisAreaAutoimmune DiseasesAutoimmunityBindingBiogenesisBiological AssayBiologyBone Marrow TransplantationBreedingCellsChIP-seqChromatinClinicalComplexDevelopmentEragrostisFOXP3 geneFamilyFamily memberFluorescenceFunctional disorderFundingGenetic TranscriptionGoalsImmuneImmune ToleranceImmunosuppressionInterleukin 2 ReceptorInterleukin-2JAK3 geneKnowledgeLifeLoxP-flanked alleleMalignant NeoplasmsMapsMediatingMessenger RNAModelingMotorMusMutationOrgan TransplantationPathway interactionsPatientsPeripheralPharmaceutical PreparationsPhenotypePositioning AttributeProductivityProteinsRNARNA BindingRNA HelicaseRNA ProcessingRNA SplicingRNA immunoprecipitation sequencingRNA-Binding ProteinsRegulationRegulatory T-LymphocyteReporterReportingRibosomesRoleSignal TransductionSiteSpliceosomesStat5 proteinSystemTestingThymus GlandTimeToxic effectTranscription Factor AP-1TranslatingTransplant RecipientsTransplantationTransplantation ToleranceUntranslated Regionsaspartylglutamatechromatin remodelingdesigneffector T cellgenome-wide analysisglutamylalaninehelicasein vivoinflammatory milieuknock-downmRNA PrecursormRNA Stabilitymembernoveloverexpressionprogramsreceptorsensorsignature moleculesingle-cell RNA sequencingstress granuletooltranscription factortranscriptometranscriptome sequencingtransplantation therapyviral RNA
项目摘要
Project Summary
Rejection remains a major hurdle to long lasting transplant survival and we aspire to uncover the
fundamental mechanisms that hinder stable allograft survival. In the last funding period, we studied the
mechanisms of Treg dysfunctions and identified BATF and BATF3 as potent repressors of Foxp3,
suppressing Foxp3 expression and Treg induction. These studies also led to the discovery of the DHX15
helicase as a critical regulator of Foxp3+Tregs, as conditional deletion of Dhx15 in Tregs resulted in a
profound depletion of Tregs in the periphery and lethal autoimmune diseases. In essence, DHX15 is an
RNA helicase (an RNA binding motor protein) and traditionally thought to be involved in RNA processing. Its
roles in the control of Tregs are unexpected and clearly reveal novel previously unknown aspects of Tregs
that are different from currently known mechanisms, and uncovering those mechanisms is the central goal
of this proposal.
Our working hypothesis is that DHX15 controls Treg identity and/or survival at peripheral sites and that its
deficiency results in either their reversion to Teff or die of apoptosis. We surmise that DHX15 may also
control Tregs at the graft site, where they must overcome the inflammatory milieu to exert suppressive
functions. We proposed 3 Aims to test this hypothesis in this application: the first Aim is to test whether
DHX15 controls Treg identity by acting as an RNA splicing factor, processing mRNAs that encode the
Foxp3 or Foxp3 controlled signature molecules in Tregs, the second Aim is to address whether DHX15
controls Tregs survival by regulating the IL-2 signaling complex, such that Tregs die of apoptosis in its
absence, and the third Aim is to examine whether DHX15 is especially important for Tregs at graft sites
where they are needed the most in promoting transplant tolerance. Overall, DHX15 is the first RNA helicase
identified thus far that controls Tregs, and the genetically modified models as well as cutting-edge
approaches we have developed put us in a unique position in dissecting mechanistically how the DHX15
helicase acts in regulating Tregs, an area of considerable importance in both basic Treg biology and Treg-
based therapies.
项目摘要
排斥反应仍然是移植肾长期存活的主要障碍,我们渴望揭开
阻碍同种异体移植物稳定存活的基本机制。在上一个资助期,我们研究了
Treg功能障碍的机制及BATF和BATF3是Foxp3的有效抑制因子,
抑制Foxp3的表达和Treg的诱导。这些研究还导致了DHX15的发现
解旋酶作为Foxp3+Tregs的关键调节因子,因为Tregs中Dhx15的条件缺失导致了
外周Tregs的严重枯竭和致命性自身免疫性疾病。从本质上讲,DHX15是一种
RNA解旋酶(一种与RNA结合的马达蛋白),传统上被认为与RNA加工有关。它的
在Tregs的控制中的角色是意想不到的,并清楚地揭示了Tregs以前不为人知的新方面
不同于目前已知的机制,而发现这些机制是中心目标
这项提议。
我们的工作假设是DHX15控制着Treg的身份和/或周围部位的存活,而且它的
缺乏会导致它们回复到TJeff或死于细胞凋亡。我们推测DHX15也可能
控制移植物部位的Tregs,它们必须克服炎症环境才能发挥抑制作用
功能。我们在这个应用中提出了3个目标来检验这一假设:第一个目标是检验
DHX15通过作为RNA剪接因子来控制Treg的身份,处理编码
Foxp3或Foxp3控制Treg中的签名分子,第二个目标是解决DHX15
通过调节IL-2信号复合体来控制Tregs的存活,使Tregs在其
第三个目的是检查DHX15是否对移植物部位的Treg特别重要
在促进移植耐受方面最需要它们的地方。总之,DHX15是第一个RNA解旋酶
到目前为止已确定的控制Tregs、转基因模型以及尖端技术的
我们开发的方法使我们处于一个独特的位置,可以机械地剖析DHX15
解旋酶在调节Treg中起作用,这在基础Treg生物学和Treg生物学中都是相当重要的领域。
以治疗为基础。
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(0)
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Xian Chang Li其他文献
An update on regulatory T cells in transplant tolerance and rejection
移植耐受与排斥中调节性 T 细胞的最新进展
- DOI:
10.1038/nrneph.2010.101 - 发表时间:
2010-08-03 - 期刊:
- 影响因子:39.800
- 作者:
Xian Chang Li;Laurence A. Turka - 通讯作者:
Laurence A. Turka
Vascularized Composite Allotransplantation Research: The Emerging Field
血管化复合同种异体移植研究:新兴领域
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:8.8
- 作者:
Bohdan Pomahac;Yolanda T. Becker;L. Cendales;S. Ildstad;Xian Chang Li;S. Schneeberger;M. Siemionow;A. Thomson;Xin Xiao Zheng;Stefan G. Tullius - 通讯作者:
Stefan G. Tullius
IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabetogenic autoimmunity in nonobese diabetic mice.
IL-2 受体靶向细胞溶解性 IL-2/Fc 融合蛋白治疗可阻断非肥胖糖尿病小鼠的糖尿病性自身免疫。
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:4.4
- 作者:
X. Zheng;A. Steele;Wayne W. Hancock;Kensaku Kawamoto;Xian Chang Li;Peter W. Nickerson;Yongsheng Li;Yan Tian;Terry B. Strom - 通讯作者:
Terry B. Strom
Facile synthesis of rare earth ions doped LiSrsub4/sub(BNsub2/sub)sub3/sub phosphors for white light-emitting diodes
用于白光发光二极管的稀土离子掺杂的 LiSr₄(BN₂)₃ 荧光粉的简便合成
- DOI:
10.1016/j.jallcom.2024.175052 - 发表时间:
2024-09-15 - 期刊:
- 影响因子:6.300
- 作者:
Wenqin Luo;Yongya Wang;Xian Chang Li;Haiyan Wu - 通讯作者:
Haiyan Wu
Blood monocyte migration to acute lung inflammation involves both CD11/CD18 and very late activation antigen-4-dependent and independent pathways.
血液单核细胞向急性肺部炎症的迁移涉及 CD11/CD18 和非常晚期激活抗原 4 依赖性和独立途径。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:4.4
- 作者:
Xian Chang Li;Masayuki Miyasaka;T. Issekutz - 通讯作者:
T. Issekutz
Xian Chang Li的其他文献
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{{ truncateString('Xian Chang Li', 18)}}的其他基金
Modulation of innate immune cells to create transplant tolerance
调节先天免疫细胞以产生移植耐受
- 批准号:
8078381 - 财政年份:2011
- 资助金额:
$ 48.45万 - 项目类别:
Modulation of innate immune cells to create transplant tolerance
调节先天免疫细胞以产生移植耐受
- 批准号:
8232053 - 财政年份:2011
- 资助金额:
$ 48.45万 - 项目类别:
Modulation of innate immune cells to create transplant tolerance
调节先天免疫细胞以产生移植耐受
- 批准号:
8628733 - 财政年份:2011
- 资助金额:
$ 48.45万 - 项目类别:
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