Investigating the Role of IL-23R in Mucosal Regulatory T Cells
研究 IL-23R 在粘膜调节 T 细胞中的作用
基本信息
- 批准号:10214607
- 负责人:
- 金额:$ 12.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-10 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAllelesAntibodiesAntigen-Presenting CellsApplications GrantsAttenuatedAutomobile DrivingBacteriaBiologicalBone MarrowCD4 Positive T LymphocytesCause of DeathCell RespirationCell physiologyCellsCellular Metabolic ProcessCellular biologyCessation of lifeChimera organismChronicClinicalColitisColon CarcinomaColorectal CancerComplementComplexCrohn&aposs diseaseDataData SetDendritic CellsDiseaseDisease remissionDisease susceptibilityEnterobacteria phage P1 Cre recombinaseEnvironmental Risk FactorEpigenetic ProcessEtiologyExhibitsFOXP3 geneFrequenciesFutureGastrointestinal tract structureGeneticGenetic TranscriptionGrantHomeostasisHumanIL12B geneImmuneImmune ToleranceImmune responseImmune systemImmunologic FactorsImmunologyImmunomodulatorsIncidenceInflammationInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInterleukin-12Interleukin-17Intestinal DiseasesIntestinesInvestigationKnowledgeLarge IntestineLesionLifeLinkLoxP-flanked alleleLymphocyteLymphoid CellMaintenanceMalignant NeoplasmsMediatingMentored Research Scientist Development AwardMentorsMetabolicMetabolic PathwayMetabolismMicrobial GeneticsMitochondriaModelingMucosal ImmunityMucous MembraneMusNatureNuclear Orphan ReceptorOrganPathogenesisPathogenicityPathway interactionsPatientsPhase III Clinical TrialsPlacebosPopulationPopulation DynamicsPostdoctoral FellowPredispositionProductionPrognosisPublishingRectal CancerRefractoryRegulatory T-LymphocyteRelapseReporterReportingResearchResearch PersonnelRespirationRetinoic Acid ReceptorRiskRoleSignal PathwaySignal TransductionSiteSourceSuperoxidesT-LymphocyteTherapeuticTranscriptUlcerative ColitisUnited StatesVariantWorkcarcinogenesiscell typecytokinedisorder riskgenome wide association studyhumanized mouseimmunoregulationimprovedin vivoinflammatory disease of the intestineinnovationinterleukin-23macrophagemouse modelpreventprogramspromoterreceptorreceptor expressionresponsesingle-cell RNA sequencingsuccessful interventionsystemic interventiontherapeutically effectivetumor
项目摘要
Project Summary
Dysregulated immune responses to luminal bacteria in the intestine are largely responsible for the chronic
nature of inflammatory bowel disease (IBD). Attenuating the inflammatory response via immunomodulators
and/or biologics represent the majority of therapeutic strategies to induce remission. However, many patients
either do not respond and those that initially do often stop responding. Restoring immune tolerance by
increasing regulatory T cell (Treg) numbers or improving Treg function may be a viable strategy to achieve
long-term remission. The PI’s K01 award has focused on strategies to expand Tregs in vivo to prevent
experimental colitis in humanized mice. In the course of these studies, the cytokine interleukin-23 (IL-23) was
upregulated in murine and human antigen presenting cells. Consistent with a role for IL-23 in IBD, variants in
IL23R have been linked to IBD susceptibility. Furthermore, a recent phase 3 clinical trial in patients with
Crohn’s disease targeted the p40 subunit of IL-23 (also shared with IL-12) and reported significant
improvement in both induction and maintenance of clinical response and remission over placebo. Although
macrophage and dendritic cells in the intestine are the source of IL-23, expression of IL-23R is generally
restricted to lymphocytes and type 3 innate lymphoid cells (ILC3s). In this proposal, we will determine the role
of IL-23R in Tregs in intestinal immune homeostasis and during inflammation using mice harboring floxed Il23r
alleles combined with a Cre recombinase driven by the endogenous Foxp3 promotor. In Aim 1, we will
determine the role of IL-23R in FOXP3+ Tregs during inflammation and inflammation-associated
carcinogenesis. In Aim 2, we will define the transcriptional, metabolic, and signaling networks/pathways
modulated by IL-23R signaling in intestinal FOXP3+ cells. Overall, these studies explore in detail how IL-23R
differentially impacts mucosal immunity and it’s role during inflammation that will inform future therapeutic
strategies for IBD and colon cancer. This proposal will further advance the independent studies of the PI and
facilitate his transition as a successful investigator and leader in the field of mucosal immunology and will
provide sufficient published and preliminary data to facilitate a highly competitive application for a R01 grant
application as an early-stage investigator.
项目摘要
肠道对肠腔细菌的免疫反应失调是慢性肠炎的主要原因
炎症性肠病(IBD)的性质。通过免疫调节剂减轻炎症反应
和/或生物制剂是诱导缓解的主要治疗策略。然而,许多患者
要么是没有回应,要么是那些最初做出回应的人经常停止回应。通过以下方式恢复免疫耐受
增加调节性T细胞(Treg)数量或改善Treg功能可能是实现
长期缓解期。PI的K01奖侧重于在体内扩大Tregs的策略,以防止
人源化小鼠实验性结肠炎。在这些研究过程中,细胞因子白介素23(IL-23)
在小鼠和人类抗原提呈细胞中上调。与IL-23在IBD中的作用一致,变种在
IL23R与IBD易感性有关。此外,最近的一项3期临床试验显示,
克罗恩病的靶点是IL-23的p40亚单位(也与IL-12相同),据报道
与安慰剂相比,在诱导和维持临床反应和缓解方面均有改善。虽然
肠内巨噬细胞和树突状细胞是IL-23的来源,IL-23R的表达一般是
仅限于淋巴细胞和3型先天淋巴样细胞(ILC3)。在这份提案中,我们将确定
IL-23R在肠道免疫稳态和炎症过程中IL-23R的表达
等位基因与内源Foxp3启动子驱动的Cre重组酶结合。在目标1中,我们将
确定IL-23R在FOXP3+树突状细胞在炎症和炎症相关过程中的作用
致癌。在目标2中,我们将定义转录、代谢和信号网络/通路
肠道FOXP3+细胞受IL-23R信号调控。总体而言,这些研究详细探讨了IL-23R是如何
对黏膜免疫的不同影响及其在炎症中的作用,将为未来的治疗提供信息
IBD和结肠癌的治疗策略。这项建议将进一步推动国际和平研究所的独立研究和
促进他转变为黏膜免疫学领域的成功研究者和领导者,并将
提供足够的已公布和初步数据,以促进竞争激烈的R01拨款申请
申请成为一名早期调查员。
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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Jeremy Allen Goettel其他文献
Jeremy Allen Goettel的其他文献
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{{ truncateString('Jeremy Allen Goettel', 18)}}的其他基金
Characterizing antibody responses to HIV-1 vaccination in next-generation immune humanized mice
表征下一代免疫人源化小鼠对 HIV-1 疫苗接种的抗体反应
- 批准号:
10673292 - 财政年份:2023
- 资助金额:
$ 12.98万 - 项目类别:
Investigating the Role of IL-23R in Mucosal Regulatory T Cells
研究 IL-23R 在粘膜调节 T 细胞中的作用
- 批准号:
10057505 - 财政年份:2020
- 资助金额:
$ 12.98万 - 项目类别:
Investigating cross-regulation of the microbiome and mucosal immune system using humanized mice
使用人源化小鼠研究微生物组和粘膜免疫系统的交叉调节
- 批准号:
9341288 - 财政年份:2015
- 资助金额:
$ 12.98万 - 项目类别:
Investigating cross-regulation of the microbiome and mucosal immune system using humanized mice
使用人源化小鼠研究微生物组和粘膜免疫系统的交叉调节
- 批准号:
9109630 - 财政年份:2015
- 资助金额:
$ 12.98万 - 项目类别:
Investigating cross-regulation of the microbiome and mucosal immune system using humanized mice
使用人源化小鼠研究微生物组和粘膜免疫系统的交叉调节
- 批准号:
9769013 - 财政年份:2015
- 资助金额:
$ 12.98万 - 项目类别:
Investigating the function of human regulatory cells in the intestinal mucosa of
研究人类肠粘膜调节细胞的功能
- 批准号:
8619514 - 财政年份:2013
- 资助金额:
$ 12.98万 - 项目类别:
Function of human regulatory cells in the intestinal mucosa of humanized mice
人类调节细胞在人源化小鼠肠粘膜中的功能
- 批准号:
8457624 - 财政年份:2013
- 资助金额:
$ 12.98万 - 项目类别:
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