Host's and microbiota's contribution to sexual dimorphism of autoimmunity
宿主和微生物群对自身免疫性二态性的贡献
基本信息
- 批准号:10608647
- 负责人:
- 金额:$ 66.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-16 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptedAdverse reactionsAffectAndrogen ReceptorAnimalsAntigensAreaAttenuatedAutoimmune DiseasesAutoimmune ProcessAutoimmunityBone MarrowBreedingCellsComputing MethodologiesDataDevelopmentDiseaseDisease ProgressionEnvironmental Risk FactorEvolutionFemaleFetusFoundationsFutureGene ExpressionGene Expression RegulationGenetic DriftGenetic ModelsGerm-FreeGnotobioticGoalsGonadal Steroid HormonesHormonalHormonesImmuneImmune signalingImmune systemInfectionInsulin-Dependent Diabetes MellitusInterferon Type IIMediatingMicrobeModelingMolecularMothersMultiple SclerosisMusMyeloid CellsNon obeseOrganismPathway interactionsPhosphoric Monoester HydrolasesPlayPregnancyPrevalenceProcessPropertyReceptor SignalingRegulationResearchResistanceRoleSclerodermaSex BiasSex ChromosomesSignal TransductionSjogren&aposs SyndromeSystemic Lupus ErythematosusSystems DevelopmentT-LymphocyteT-cell receptor repertoireTestingThymus GlandTimeVaccinationcell typecommensal microbesdiabeticexperimental studyfeedingflexibilityhormone regulationimprintmalemicrobialmicrobiotamicroorganismpreventsexsexual dimorphismtimelinetranscription factor
项目摘要
Many of major autoimmune diseases are sexually dimorphic. Systemic Lupus Erythematosus (SLE),
scleroderma, multiple sclerosis, Sjogren’s syndrome, and some forms of Type 1 diabetes (T1D) are primarily
occurring in females. It has been attributed to multiple factors including expression of the genes encoded by
sex chromosomes, hormonal regulation of gene expression, and lately to unexpected regulation by commensal
microbiota. Thus, understanding of sexual dimorphism of diseases requires that the problem be approached by
a combination of different strategies. In this proposal, we take advantage of our abilities to perform state of the
art experiments using genetically modified and gnotobiotic animals with original and constantly developing
computational methods. Our preliminary data demonstrates the efficiency of such an integrative approach to
the problem. We have suggested a ‘dual signal’ model of autoimmunity involving regulation by microbes and
sex hormones. Accordingly, hormonal and microbial influences do not have to be simultaneous: they may be
important at different stages of development or disease progression. We are focusing on T cell-intrinsic and T-
cell-extrinsic effects of Androgen Receptor (AR) and the mechanisms of microbiota’s effect on T1D
development. Given the complexity of the problem, we plan to pursue several carefully selected goals that will
continue to lay foundation for the future expansion of research in this important area.
Specific Aim 1. Determine the input of T cell-intrinsic and T cell-extrinsic mechanisms in the sexual
dimorphism of T1D.
1.1. Determine whether all cells involved in AR-mediated protection from T1D are of bone marrow origin;
1.2. Define the role of myeloid cells in male protection from T1D;
1.3. Test the contribution of myeloid cells in T cell transfer experiments;
1.4. Test a role that transcription factor AIRE plays in sexual dimorphism of T1D.
Specific Aim 2. Investigate the influence of AR signaling on T cell selection and function
2.1. Determine the influence of AR on the TCR repertoires;
2.2. Determine how the properties of the TCR affect the influence of AR on repertoire selection;
2.3. Study the role of AR in regulation of interferon gamma (IFNg) related to autoimmunity;
2.4. Study the role of AR in regulation of the IFNg locus;
Specific Aim 3. Determine where and when the microbiota amplifies AR effects on T1D development.
3.1. Test T1D development in GF animals with conditional AR deficiencies;
3.2. Determine whether microbes contribute to changes in immune cells properties during their development;
3.3. Establish the timeline to imprinting males to become resistant to T1D by the microbiota;
3.4. Determine which immune-related pathways are affected by the microbiota.
许多主要的自身免疫性疾病都是性二型的。系统性红斑狼疮
硬皮病、多发性硬化症、干燥综合征和某些形式的1型糖尿病(T1D)主要是
发生在雌性体内。它被归因于多种因素,包括编码的基因的表达
性染色体,荷尔蒙对基因表达的调节,以及最近共生对意想不到的调节
微生物区系。因此,对疾病的性别二型性的理解需要通过
不同策略的组合。在这项提议中,我们利用我们的能力来执行
利用原创和不断发展的转基因和灵知生菌动物进行艺术实验
计算方法。我们的初步数据证明了这种综合方法的有效性
问题就在这里。我们提出了自身免疫的“双信号”模型,该模型涉及微生物和
性激素。因此,荷尔蒙和微生物的影响不必同时发生:它们可能是同时发生的。
在发育的不同阶段或疾病发展的不同阶段很重要。我们关注的是T细胞固有的和T-
雄激素受体(AR)的细胞外效应及微生物区系对T1D影响的机制
发展。考虑到问题的复杂性,我们计划追求几个精心挑选的目标,这些目标将
继续为今后这一重要领域的研究拓展奠定基础。
具体目标1.确定T细胞内在机制和T细胞外在机制在性行为中的输入
T1D的二形性。
1.1.确定是否所有参与AR介导的T1D保护作用的细胞都来自骨髓;
1.2.明确髓系细胞在男性T1D保护中的作用;
1.3.检测髓系细胞在T细胞转移实验中的作用;
1.4.检测转录因子AIRE在T1D性二型性中的作用。
具体目的2.研究AR信号对T细胞选择和功能的影响
2.1.确定AR对TCR曲目的影响;
2.2.确定TCR的属性如何影响AR对曲目选择的影响;
2.3.研究AR在自身免疫相关干扰素-γ(IFNG)调节中的作用;
2.4.研究AR在IFNG基因位点调控中的作用;
具体目标3.确定微生物群何时何地放大AR对T1D发育的影响。
3.1.检测有条件性AR缺陷的GF动物的T1D发育;
3.2.确定微生物在发育过程中是否对免疫细胞特性的变化起到促进作用;
3.3.建立通过微生物区系印记雄性变得对T1D产生抗性的时间表;
3.4.确定哪些免疫相关途径受到微生物区系的影响。
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 }}
ALEXANDER V CHERVONSKY其他文献
ALEXANDER V CHERVONSKY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('ALEXANDER V CHERVONSKY', 18)}}的其他基金
Enhancement of autoimmunity in type 1 diabetes by gluten
麸质增强 1 型糖尿病的自身免疫能力
- 批准号:
10390844 - 财政年份:2021
- 资助金额:
$ 66.32万 - 项目类别:
Enhancement of autoimmunity in type 1 diabetes by gluten
麸质增强 1 型糖尿病的自身免疫能力
- 批准号:
10490911 - 财政年份:2021
- 资助金额:
$ 66.32万 - 项目类别:
Enhancement of autoimmunity in type 1 diabetes by gluten
麸质增强 1 型糖尿病的自身免疫能力
- 批准号:
10680525 - 财政年份:2021
- 资助金额:
$ 66.32万 - 项目类别:
Host's and microbiota's contribution to sexual dimorphism of autoimmunity
宿主和微生物群对自身免疫性二态性的贡献
- 批准号:
9388410 - 财政年份:2017
- 资助金额:
$ 66.32万 - 项目类别:
Host's and microbiota's contribution to sexual dimorphism of autoimmunity
宿主和微生物群对自身免疫性二态性的贡献
- 批准号:
10216963 - 财政年份:2017
- 资助金额:
$ 66.32万 - 项目类别:
Commensal microbes and sexual dimorphism in autoimmunity
自身免疫中的共生微生物和性别二态性
- 批准号:
8643918 - 财政年份:2014
- 资助金额:
$ 66.32万 - 项目类别:
Commensal microbes and sexual dimorphism in autoimmunity
自身免疫中的共生微生物和性别二态性
- 批准号:
8828075 - 财政年份:2014
- 资助金额:
$ 66.32万 - 项目类别:
相似海外基金
How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
- 批准号:
2315783 - 财政年份:2023
- 资助金额:
$ 66.32万 - 项目类别:
Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
- 批准号:
2719534 - 财政年份:2022
- 资助金额:
$ 66.32万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633211 - 财政年份:2020
- 资助金额:
$ 66.32万 - 项目类别:
Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
- 批准号:
20K01113 - 财政年份:2020
- 资助金额:
$ 66.32万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2436895 - 财政年份:2020
- 资助金额:
$ 66.32万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633207 - 财政年份:2020
- 资助金额:
$ 66.32万 - 项目类别:
Studentship
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
- 批准号:
426559561 - 财政年份:2019
- 资助金额:
$ 66.32万 - 项目类别:
Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
- 批准号:
2236701 - 财政年份:2019
- 资助金额:
$ 66.32万 - 项目类别:
Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
- 批准号:
19K01745 - 财政年份:2019
- 资助金额:
$ 66.32万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
- 批准号:
415543446 - 财政年份:2019
- 资助金额:
$ 66.32万 - 项目类别:
Research Fellowships