Mechanisms controlling Foxp3 expression and regulatory T cell homeostasis
控制 Foxp3 表达和调节性 T 细胞稳态的机制
基本信息
- 批准号:8658598
- 负责人:
- 金额:$ 45.59万
- 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:2013-06-01 至 2014-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdoptedAntigensAttenuatedAutoimmune DiseasesAutoimmune ProcessAutoimmunityBiological AssayBiologyCandidate Disease GeneCellsCodeControl LocusDefectDendritic CellsDevelopmentEquilibriumFunctional RNAGenerationsGenomicsGoalsHomeostasisHumanImmuneImmune responseImmune systemIndividualInsulin-Dependent Diabetes MellitusKnock-outKnockout MiceLeadLymphocyte FunctionLymphocytic choriomeningitis virusMaintenanceMalignant NeoplasmsMolecularMusNamesOutcomePathway interactionsPeripheralPhenotypePlayPopulationPopulation DynamicsProtein BindingRegulatory T-LymphocyteRoleSequence AnalysisShapesSignal PathwaySystemT-LymphocyteTechniquesTestingTherapeuticThymectomyTransforming Growth Factor betaTransgenic Micebasechimeric antibodychromatin immunoprecipitationfollow-upimmunogenicimmunopathologyin vivoinsightmouse modelpathogenpreventsmall hairpin RNAtranscription factor
项目摘要
DESCRIPTION (provided by applicant): A functional immune system has to maintain a delicate balance between effective elimination of foreign pathogens and minimizing collateral damage to the host. Regulatory T cells (Tregs), a subset of T lymphocytes, function as suppressor of the immune system and play a critical role in maintaining immune homeostasis. Defects in Treg function lead to autoimmune diseases and immunopathology in humans and mice. One of the milestones in Treg biology field was the identification of transcription factor Foxp3 as an essential regulator of Treg development and function. The goal of this project is to elucidate the molecular mechanisms that control Foxp3 expression, which will determine how regulatory T cells are generated and maintained. By comparing Foxp3 genomic sequences of different species, Dr. Zheng and colleagues identified three intronic regions that are evolutionarily conserved, which they named CNS1, 2, and 3 (Conserved Non- coding Sequence). They hypothesized that these CNS regions could play an important role in regulating Foxp3 expression, and proceeded to knockout individual Foxp3 CNS regions in mice. Each of the three CNS knockout mice showed different defects in their Treg population, suggesting they play different roles in control of Foxp3 expression. CNS3 is required for thymic development of Tregs, whereas CNS1 is involved in TGF-beta dependent peripheral conversion of Tregs. Most interestingly, CNS2 plays a role in maintaining Foxp3 expression and stabilizing Treg lineage. In the current proposal, Dr. Zheng's group will follow up on the initial characterization of the Foxp3 CNS knockout mice to perform a detailed study on how the CNS regions control regulatory T cell homeostasis at both cellular and molecular levels. First, they will use more physiologically relevant mouse models to investigate the role of Foxp3 CNS2 in maintenance of natural Treg lineage stability and perform TCR repertoire study to examine the flux of Treg subsets in the absence of CNS2 (Aim 1). Second, they will explore the role of Foxp3 CNS regions in generation and maintenance of antigen-specific Tregs induced in vivo by anti-DEC205 chimeric antibody (Aim 2). Lastly, they plan to use a modified chromatin immunoprecipitation assay to identify proteins bound to CNS regions that regulate Foxp3 expression (Aim 3). The study proposed here will provide more insight on mechanisms controlling Treg homeostasis, and potentially generate new avenues to manipulate Tregs to attenuate or augment the amplitude of immune response for treatment of autoimmune diseases and cancer.
描述(由申请人提供):功能性免疫系统必须在有效消除外来病原体和尽量减少对宿主的附带损害之间保持微妙的平衡。调节性T细胞(Regulatory T cells,Tcells)是T淋巴细胞的一个亚群,是免疫系统的抑制因子,在维持免疫稳态中起重要作用。Treg功能缺陷导致人类和小鼠的自身免疫性疾病和免疫病理学。Treg生物学领域的里程碑之一是转录因子Foxp 3作为Treg发育和功能的重要调节因子的鉴定。该项目的目标是阐明控制Foxp 3表达的分子机制,这将决定如何产生和维持调节性T细胞。通过比较不同物种的Foxp 3基因组序列,Zheng博士及其同事确定了三个进化上保守的内含子区域,他们将其命名为CNS 1,2和3(保守的非编码序列)。他们假设这些中枢神经系统区域在调节Foxp 3表达中发挥重要作用,并继续敲除小鼠中的单个Foxp 3中枢神经系统区域。三只CNS敲除小鼠中的每一只都在其Treg群体中显示出不同的缺陷,这表明它们在Foxp 3表达的控制中发挥着不同的作用。CNS 3是胸腺发育所必需的,而CNS 1参与TGF-β依赖性外周转化。最有趣的是,CNS 2在维持Foxp 3表达和稳定Treg谱系中起作用。在目前的提案中,Zheng博士的团队将跟进Foxp 3 CNS敲除小鼠的初步特征,以详细研究CNS区域如何在细胞和分子水平上控制调节性T细胞稳态。首先,他们将使用生理学上更相关的小鼠模型来研究Foxp 3 CNS 2在维持天然Treg谱系稳定性中的作用,并进行TCR库研究以检查在不存在CNS 2的情况下Treg亚群的通量(Aim 1)。第二,他们将探索Foxp 3 CNS区域在由抗DEC 205嵌合抗体体内诱导的抗原特异性Tclase的产生和维持中的作用(Aim 2)。最后,他们计划使用改良的染色质免疫沉淀试验来鉴定与调节Foxp 3表达的CNS区域结合的蛋白质(Aim 3)。本文提出的研究将为控制Treg稳态的机制提供更多的见解,并可能产生新的途径来操纵Treg以减弱或增强免疫应答的幅度,用于治疗自身免疫性疾病和癌症。
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 }}
Ye Zheng其他文献
Ye Zheng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('Ye Zheng', 18)}}的其他基金
Define the role of REV-ERB in colonic RORgt+ regulatory T cells
定义 REV-ERB 在结肠 RORgt 调节性 T 细胞中的作用
- 批准号:
10753360 - 财政年份:2023
- 资助金额:
$ 45.59万 - 项目类别:
A novel role of hypusination in controlling regulatory T cell function
hypusination 在控制调节性 T 细胞功能中的新作用
- 批准号:
10356173 - 财政年份:2021
- 资助金额:
$ 45.59万 - 项目类别:
Investigating the interplay of structural, molecular and spatial mechanisms that control SHP2 activity downstream of PD1
研究控制 PD1 下游 SHP2 活性的结构、分子和空间机制的相互作用
- 批准号:
10002277 - 财政年份:2018
- 资助金额:
$ 45.59万 - 项目类别:
Treg development and function controlled by cis-regulatory circuits
由顺式调节电路控制的 Treg 发育和功能
- 批准号:
10318638 - 财政年份:2014
- 资助金额:
$ 45.59万 - 项目类别:
Regulatory T cell lineage stability controlled by Foxp3 CNS2
Foxp3 CNS2 控制的调节性 T 细胞谱系稳定性
- 批准号:
9197261 - 财政年份:2014
- 资助金额:
$ 45.59万 - 项目类别:
Treg development and function controlled by cis-regulatory circuits
由顺式调节电路控制的 Treg 发育和功能
- 批准号:
10092894 - 财政年份:2014
- 资助金额:
$ 45.59万 - 项目类别:
相似国自然基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
- 批准号:2022J011295
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
- 批准号:30801055
- 批准年份:2008
- 资助金额:19.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Initial clinical evaluation of attenuated Shigella flexneri 2a live vector expressing enterotoxigenic Escherichia coli antigens, strain CVD 1208S-122.
对表达产肠毒素大肠杆菌抗原(CVD 1208S-122 菌株)的福氏志贺氏菌 2a 活载体进行初步临床评估。
- 批准号:
10407441 - 财政年份:2020
- 资助金额:
$ 45.59万 - 项目类别:
Initial clinical evaluation of attenuated Shigella flexneri 2a live vector expressing enterotoxigenic Escherichia coli antigens, strain CVD 1208S-122.
对表达产肠毒素大肠杆菌抗原(CVD 1208S-122 菌株)的福氏志贺氏菌 2a 活载体进行初步临床评估。
- 批准号:
10212188 - 财政年份:2020
- 资助金额:
$ 45.59万 - 项目类别:
Identification of protective Lyme disease antigens using live attenuated vaccines
使用减毒活疫苗鉴定保护性莱姆病抗原
- 批准号:
9173245 - 财政年份:2016
- 资助金额:
$ 45.59万 - 项目类别:
Identification of protective Lyme disease antigens using live attenuated vaccines
使用减毒活疫苗鉴定保护性莱姆病抗原
- 批准号:
9275338 - 财政年份:2016
- 资助金额:
$ 45.59万 - 项目类别:
Identification of protective Lyme disease antigens using live attenuated vaccines
使用减毒活疫苗鉴定保护性莱姆病抗原
- 批准号:
9917694 - 财政年份:2016
- 资助金额:
$ 45.59万 - 项目类别:
Live Attenuated Recombinant Bacterial Delivery of Polysaccharide Vaccine Antigens
多糖疫苗抗原的活减毒重组细菌递送
- 批准号:
7629589 - 财政年份:2006
- 资助金额:
$ 45.59万 - 项目类别:
Live Attenuated Recombinant Bacterial Delivery of Polysaccharide Vaccine Antigens
多糖疫苗抗原的活减毒重组细菌递送
- 批准号:
7150146 - 财政年份:2006
- 资助金额:
$ 45.59万 - 项目类别:
Live Attenuated Recombinant Bacterial Delivery of Polysaccharide Vaccine Antigens
多糖疫苗抗原的活减毒重组细菌递送
- 批准号:
8147892 - 财政年份:2006
- 资助金额:
$ 45.59万 - 项目类别:
Live Attenuated Recombinant Bacterial Delivery of Polysaccharide Vaccine Antigens
多糖疫苗抗原的活减毒重组细菌递送
- 批准号:
7432599 - 财政年份:2006
- 资助金额:
$ 45.59万 - 项目类别:
Live Attenuated Recombinant Bacterial Delivery of Polysaccharide Vaccine Antigens
多糖疫苗抗原的活减毒重组细菌递送
- 批准号:
7236052 - 财政年份:2006
- 资助金额:
$ 45.59万 - 项目类别: