Retinoic acid in gut immune homestatis and infection
视黄酸在肠道免疫稳态和感染中的作用
基本信息
- 批准号:9205215
- 负责人:
- 金额:$ 59.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-01-15 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAntigensArchitectureAreaAutoimmunityBackBacteriaBindingBiologicalCD8-Positive T-LymphocytesCD8B1 geneCell Differentiation processCell LineageCell SurvivalCellsCellular biologyCommunicable DiseasesDataDevelopmentDiseaseDisease modelDominant-Negative MutationEmployee StrikesEnhancersEquilibriumEragrostisEventFOXP3 geneFunctional disorderGenesGenetic ModelsGraft RejectionHematopoieticHost resistanceIL17 geneImmuneImmune responseImmunityImmunizationImpairmentIn VitroInfectionInfiltrationInflammatoryInflammatory Bowel DiseasesLeukocytesListeria monocytogenesLiteratureMaintenanceMemoryMolecularMonitorMucosal ImmunityMusOralPathogenicityPathway interactionsPhenotypePredispositionPreschool ChildProtein IsoformsPublishingRegulationRegulatory T-LymphocyteReportingRepressionResistanceRoleSTAT4 geneSignal TransductionSpecific qualifier valueSupporting CellSyndromeSystemic infectionT-LymphocyteTh1 CellsTimeTissuesTretinoinVitamin AWorkadaptive immune responsecomparativegenetic approachimprovedin vivomucosal sitenovelnovel therapeuticsoral infectionoverexpressionpathogenpreventprogramspublic health relevancereceptorresponseretinoic acid receptor alphatranscriptome
项目摘要
DESCRIPTION (provided by applicant): We propose that retinoic acid (RA) regulates mucosal adaptive immune response controlling the fate of committed (Th1, Treg, CD8eff) T cells. In the absence of RA signaling, we show that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes as well as repressing genes that instruct Th17 cell fate. Our studies identify RA-RARα as a key component of the regulatory network governing Th1 cell fate and define a new paradigm of Th1aTh17 differentiation. These findings have important implications for gut immunity in which dysregulated Th1-Th17 responses are observed. We further show that ablation of RA signaling in the Foxp3 lineage ablates in vivo Treg function. Finally, impairment of RA signaling of through specific receptor isoforms limits CD8 T cell survival and differentiation. As such, we propose that these functions of RA are prominent in its role in host resistance to infectious disease. Using genetic models that allow lineage specific control of RA signaling in vivo we will: 1. Define the role of RA in Th1 stability
and repression of Th1aTh17 differentiation in the gut in vivo. We show that RA controls the level of T-bet expression in Th1 T cells and as such controls Th1 lineage maintenance. Furthermore, we show that T cells which are deprived of an RA signal develop into double positive, IL17+, IFNgLow T cells and Th17 cells. RARa CHIPseq studies and transcriptome analysis have identified for the first time, direct targets for RAR regulation in T cells and provie important biological leads as to how RA programs T cell lineage maintenance and phenotype. Finally, given the fact that RA tissue levels control critical events in T cell commitment, we will
exploit the use of genetic models where RA synthesis can be specifically ablated in the lineage of choice to determine the RA-synthesizing cells that support T cell fate in vivo. 2. Define the role of RA in sustaining Treg function in the gut. Selective silencing of RA signaling in the Foxp3
lineage, results in the emergence of a striking inflammatory syndrome that we hypothesize is due to Treg lineage instability and dysfunction. It is proposed that both natural and adaptive Treg function is ablated and the underlying cellular and molecular mechanisms will be addressed. 3. Understanding the role of RA in CD8 lineage commitment in the gut. We have defined specific distinctive contributions of RARa vs RARb in CD8 T cell biology. In CD8+ T cells, RARa is critical for T cell survival and RARb is critical for antigen-specific T cell expansion. These approaches provide the novel and exciting opportunity to fully define the role of RAR isoforms in CD8+ T cell stability, survival, expansion and development of memory. A comprehensive set of studies is presented which will represent the first to track and quantify the antigen-specific CD8+ T cell responses in the gut.
描述(申请人提供):我们建议维甲酸(RA)调节粘膜获得性免疫反应,控制承诺(Th1,Treg,CD8effT细胞)的命运。在没有RA信号的情况下,我们发现RA通过其受体RARα维持Th1谱系特定基因的稳定表达,以及抑制指示Th17细胞命运的基因。我们的研究确认RA-RARα是控制Th1细胞命运的调控网络的关键组成部分,并定义了Th1aTh17分化的新范式。这些发现对肠道免疫有重要意义,在肠道免疫中观察到Th1-Th17反应失调。我们进一步证明,在体内,Foxp3谱系中RA信号的消融会消融Treg功能。最后,通过特定受体亚型的RA信号受损限制了CD8T细胞的存活和分化。因此,我们认为RA的这些功能在宿主抵抗传染病方面的作用是突出的。使用允许在体内对RA信号进行谱系特异性控制的遗传模型,我们将:1.确定RA在Th1稳定性中的作用
体内抑制Th1a、、Th17的分化。我们发现RA控制Th1T细胞中T-bet的表达水平,并因此控制Th1谱系的维持。此外,我们还发现,失去RA信号的T细胞发育成双阳性、IL17+、IFNgLow T细胞和Th17细胞。RARA CHIPseq研究和转录组分析首次确定了T细胞中RAR调节的直接靶点,并为RA如何规划T细胞谱系维持和表型提供了重要的生物学线索。最后,考虑到RA组织水平控制T细胞承诺的关键事件的事实,我们将
利用遗传模型,其中RA合成可以在选择的谱系中被特异性地消融,以确定支持体内T细胞命运的RA合成细胞。2.明确RA在维持肠道Treg功能中的作用。Foxp3中RA信号的选择性沉默
家系,导致一种显著的炎症综合征的出现,我们假设是由于Treg血统的不稳定和功能障碍。有人提出,自然和适应性Treg功能都被消融,其潜在的细胞和分子机制将被解决。3.了解RA在肠道CD8谱系承诺中的作用。我们已经确定了RARa和RARb在CD8T细胞生物学中的独特贡献。在CD8+T细胞中,RARa对T细胞的存活至关重要,而RARb对抗原特异性T细胞的增殖至关重要。这些方法提供了新的和令人兴奋的机会,以充分确定RAR亚型在CD8+T细胞稳定、存活、扩展和记忆发育中的作用。提出了一套全面的研究,这将是第一次跟踪和量化肠道中抗原特异的CD8+T细胞反应。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
RANDOLPH J. NOELLE其他文献
RANDOLPH J. NOELLE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('RANDOLPH J. NOELLE', 18)}}的其他基金
Targeting VISTA eradicates large, established PD-1/CTLA-4 resistant tumors
靶向 VISTA 根除大型、已确定的 PD-1/CTLA-4 耐药肿瘤
- 批准号:
9917740 - 财政年份:2017
- 资助金额:
$ 59.46万 - 项目类别:
Targeting VISTA eradicates large, established PD-1/CTLA-4 resistant tumors
靶向 VISTA 根除大型、已确定的 PD-1/CTLA-4 耐药肿瘤
- 批准号:
10170281 - 财政年份:2017
- 资助金额:
$ 59.46万 - 项目类别:
Retinoic acid in gut immune homestatis and infection
视黄酸在肠道免疫稳态和感染中的作用
- 批准号:
8913568 - 财政年份:2015
- 资助金额:
$ 59.46万 - 项目类别:
VISTA, a novel regulator of immunity and autoimmunity
VISTA,一种新型免疫和自身免疫调节剂
- 批准号:
8840881 - 财政年份:2012
- 资助金额:
$ 59.46万 - 项目类别:
VISTA, a novel regulator of immunity and autoimmunity
VISTA,一种新型免疫和自身免疫调节剂
- 批准号:
8463984 - 财政年份:2012
- 资助金额:
$ 59.46万 - 项目类别:
Validation of a Negative Regulator as a Novel Therapy for Autoimmune Disease
负调节剂作为自身免疫性疾病新疗法的验证
- 批准号:
8314301 - 财政年份:2012
- 资助金额:
$ 59.46万 - 项目类别:
Validation of a Negative Regulator as a Novel Therapy for Autoimmune Disease
负调节剂作为自身免疫性疾病新疗法的验证
- 批准号:
8461514 - 财政年份:2012
- 资助金额:
$ 59.46万 - 项目类别:
VISTA, a novel regulator of immunity and autoimmunity
VISTA,一种新型免疫和自身免疫调节剂
- 批准号:
8387505 - 财政年份:2012
- 资助金额:
$ 59.46万 - 项目类别:
Safe and effective anti CD154 antibodies for therapeutic intervention
用于治疗干预的安全有效的抗 CD154 抗体
- 批准号:
8523637 - 财政年份:2012
- 资助金额:
$ 59.46万 - 项目类别:
Safe And Effective Anti-CD154 Antibodies For Therapeutic Intervention
用于治疗干预的安全有效的抗 CD154 抗体
- 批准号:
8394297 - 财政年份:2012
- 资助金额:
$ 59.46万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 59.46万 - 项目类别:
Research Grant