The role of AIM2 in T cell-mediated autoimmunity
The role of AIM2 in T cell-mediated autoimmunity
批准号:
10321613
负责人:
Roland M Tisch
金额:
$38.88万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-01-05 至 2023-12-31
关键词:
AIM2 geneAKT Signaling PathwayAffectAntigen-Presenting CellsAntigensAutoimmune DiseasesAutoimmune ProcessAutoimmunityAutomobile DrivingBindingCD4 Positive T LymphocytesCell CompartmentationCell DeathCell physiologyCellsCellular immunotherapyComplexDNADNA-dependent protein kinaseDefectDendritic CellsDevelopmentDiabetes MellitusEragrostisEventExhibitsFoundationsGoalsHomeostasisHost DefenseHumanHypersensitivityImmuneImmunotherapyInbred NOD MiceInflammasomeInflammationInsulin-Dependent Diabetes MellitusInterleukin-18Malignant NeoplasmsMediatingMediator of activation proteinMindModelingNatural ImmunityPI3K/AKTPathogenicityPathway interactionsPeripheralPhenotypePhosphorylationProductionPropertyProto-Oncogene Proteins c-aktRegulationRoleSelf ToleranceSignal PathwaySignal TransductionStimulusT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticThymic epithelial cellThymus GlandTissuesWorkbasecentral tolerancediabetogenicds-DNAimmunoregulationinsightnegative affectnovelpathogenpathogenic microbeperipheral tolerancepreventresponsesensor
中文摘要
摘要/摘要
T细胞介导的自身免疫性疾病,如1型糖尿病(T1D),是由于复杂的事件导致的
中枢和外周耐受性失调。确定调节自我容忍的机制至关重要
了解自身免疫过程以及合理开发免疫疗法以预防
治疗T1D和其他T细胞介导的自身免疫性疾病。
这一应用是基于我们新的观察结果,即NOD小鼠缺乏AIM2炎症小体
分子仍未患上糖尿病。AIM2是一种参与宿主防御的细胞质免疫感受器。在绑定时
来自微生物病原体的双链DNA,AIM2组装成一个炎症体复合体,驱动
促炎因子IL-1bβ和IL-18的产生,以及由下垂引起的细胞死亡。最近的研究表明,
然而,AIM2已经证明了AIM2可以通过一个
不依赖于炎性小体激活的非锥形通路。在这里,AIM2起否定的作用
PI3K/AKT信号通路中的激酶DNA--PK调节因子。
我们发现,AIM2缺陷的NOD小鼠中糖尿病的缺乏也独立于炎症体的激活。
此外,有证据表明,在aim2基因缺陷的NOD小鼠中,bβ细胞的自身免疫被多个
胸腺抗原提呈细胞、外周血树突状细胞功能及T细胞亚群的影响机制
差异化。我们假设AIM2是调控PI3K/DNA-PK/AKT-的关键检查点。
依赖刺激和细胞成熟/分化影响自身耐受性和糖尿病的发生
回应。我们的目标是定义AIM2调节自我耐受的关键机制。考虑到这一点,
具体目标1将集中在AIM2对延髓胸腺上皮细胞刺激功能的影响和
胸腺树突状细胞。特异性目标2将确定AIM2在调节树突状细胞致炎中的作用
而不是耐受性功能。最后,《特定目标3》将调查AIM2如何控制
致病T细胞亚群分化。这项工作有望为深入了解新的机制和
调节中枢和外周自我耐受的途径,以及靶向
用于治疗目的的AIM2途径。
英文摘要
SUMMARY/ABSTRACT
T cell-mediated autoimmune diseases such as Type 1 diabetes (T1D) are due to complex events leading to
dysregulation of central and peripheral tolerance. Defining the mechanisms regulating self-tolerance are critical
for understanding the autoimmune process as well as for rational development of immunotherapies to prevent
and treat T1D and other T cell-mediated autoimmune diseases.
This application is based on our novel observation that NOD mice deficient in the AIM2 inflammasome
molecule remain diabetes-free. AIM2 is a cytoplasmic immune sensor involved in host defense. Upon binding
double stranded DNA from a microbial pathogen, AIM2 assembles into an inflammasome complex that drives
the production of proinflammatory IL-1bβ and IL-18, and pyroptosis-mediated cell death. Recent studies,
however, have demonstrated that AIM2 can serve a regulatory function outside of host defense via a
nonconical pathway that is independent of inflammasome activation. Here, AIM2 functions as a negative
regulator of the kinase DNA-PK in the PI3K/AKT signaling pathway.
We find that the lack of diabetes in AIM2-deficient NOD mice is also independent of inflammasome activation.
Furthermore, evidence suggests that bβ cell autoimmunity in AIM2-deficient NOD mice is blocked by multiple
mechanisms affecting thymic antigen presenting cells, peripheral dendritic cell function and T cell subset
differentiation. We hypothesize that AIM2 serves as a key checkpoint in regulating PI3K/DNA-PK/AKT-
dependent stimuli and cellular maturation/differentiation, which impacts self-tolerance and the diabetogenic
response. Our goal is to define the key mechanisms by which AIM2 regulates self-tolerance. With this in mind,
Specific Aim 1 will focus on AIM2 effects on the stimulatory function of medullary thymic epithelial cells and
thymic dendritic cells. Specific Aim 2 will define the role of AIM2 in regulating dendritic cell proinflammatory
versus tolerogenic function. Finally, Specific Aim 3 will investigate how AIM2 controls the efficiency of
pathogenic T cell subset differentiation. This work is expected to provide insight into new mechanisms and
pathways by which central and peripheral self-tolerance are regulated, as well as a foundation to target the
AIM2 pathway for therapeutic purposes.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3389/fimmu.2020.624568
发表时间:
2020
期刊:
Frontiers in immunology
影响因子:
7.3
作者:
[Ke Q, Kroger CJ, Clark M, Tisch RM]
通讯作者:
Tisch RM
DOI:
10.3389/fimmu.2023.1154552
发表时间:
2023
期刊:
Frontiers in immunology
影响因子:
7.3
作者:
[]
通讯作者:
Enhancing antigen-based therapy for T1D by T cell coreceptor tuning
-
批准号:10593245
-
项目类别:
-
资助金额:$23.33万
-
财政年份:2022
-
负责人:Roland M Tisch
-
依托单位:
ICES-based Pulsed Field Electromagnetic Field Therapy for Autoimmunity
-
批准号:9903662
-
项目类别:
-
资助金额:$23.33万
-
财政年份:2020
-
负责人:Roland M Tisch
-
依托单位:
ICES-based Pulsed Field Electromagnetic Field Therapy for Autoimmunity
-
批准号:10079462
-
项目类别:
-
资助金额:$19.44万
-
财政年份:2020
-
负责人:Roland M Tisch
-
依托单位:
Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy
-
批准号:10395438
-
项目类别:
-
资助金额:$38.88万
-
财政年份:2019
-
负责人:Roland M Tisch
-
依托单位:
Thymic and peripheral regulation of autoreactive T cells by coreceptor therapy
-
批准号:10623181
-
项目类别:
-
资助金额:$38.88万
-
财政年份:2019
-
负责人:Roland M Tisch
-
依托单位:
The role of AIM2 in T cell-mediated autoimmunity
-
批准号:10083178
-
项目类别:
-
资助金额:$38.88万
-
财政年份:2019
-
负责人:Roland M Tisch
-
依托单位:
Combinatorial beta Cell-Specific Cytokine Therapy to Reverse Type I Diabetes
-
批准号:8911506
-
项目类别:
-
资助金额:$39.14万
-
财政年份:2015
-
负责人:Roland M Tisch
-
依托单位:
Combinatorial Beta Cell-Specific Cytokine Therapy to Reverse Type I Diabetes
-
批准号:9240623
-
项目类别:
-
资助金额:$37.84万
-
财政年份:2015
-
负责人:Roland M Tisch
-
依托单位:
Islet-Specific Tolerance Induced by T Cell Co-Receptor Therapy in Type 1 Diabetes
-
批准号:8725412
-
项目类别:
-
资助金额:$33.25万
-
财政年份:2014
-
负责人:Roland M Tisch
-
依托单位:
Islet-Specific Tolerance Induced by T Cell Co-Receptor Therapy in Type 1 Diabetes
-
批准号:8829828
-
项目类别:
-
资助金额:$33.25万
-
财政年份:2014
-
负责人:Roland M Tisch
-
依托单位:
A Novel Approach of beta Cell Replacement to Reverse Type I Diabetes in NOD Mice
-
批准号:8299241
-
项目类别:
-
资助金额:$21.88万
-
财政年份:2012
-
负责人:Roland M Tisch
-
依托单位:
A Novel Approach of beta Cell Replacement to Reverse Type I Diabetes in NOD Mice
-
批准号:8418702
-
项目类别:
-
资助金额:$18.18万
-
财政年份:2012
-
负责人:Roland M Tisch
-
依托单位:
Age-Dependent Thymic Events and the Development of Autoimmune T Cells in NOD Mice
-
批准号:8064706
-
项目类别:
-
资助金额:$36.36万
-
财政年份:2010
-
负责人:Roland M Tisch
-
依托单位:
Age-Dependent Thymic Events and the Development of Autoimmune T Cells in NOD Mice
-
批准号:8660598
-
项目类别:
-
资助金额:$36.36万
-
财政年份:2010
-
负责人:Roland M Tisch
-
依托单位:
Age-Dependent Thymic Events and the Development of Autoimmune T Cells in NOD Mice
-
批准号:8469325
-
项目类别:
-
资助金额:$34.18万
-
财政年份:2010
-
负责人:Roland M Tisch
-
依托单位:
Age-Dependent Thymic Events and the Development of Autoimmune T Cells in NOD Mice
-
批准号:7984541
-
项目类别:
-
资助金额:$36.72万
-
财政年份:2010
-
负责人:Roland M Tisch
-
依托单位:
Age-Dependent Thymic Events and the Development of Autoimmune T Cells in NOD Mice
-
批准号:8279437
-
项目类别:
-
资助金额:$36.36万
-
财政年份:2010
-
负责人:Roland M Tisch
-
依托单位:
Reversal of Type I Diabetes in NOD Mice
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批准号:7653977
-
项目类别:
-
资助金额:$29.42万
-
财政年份:2009
-
负责人:Roland M Tisch
-
依托单位:
Reversal of Type I Diabetes in NOD Mice
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批准号:8235079
-
项目类别:
-
资助金额:$28.85万
-
财政年份:2009
-
负责人:Roland M Tisch
-
依托单位:
Reversal of Type I Diabetes in NOD Mice
-
批准号:7840514
-
项目类别:
-
资助金额:$29.14万
-
财政年份:2009
-
负责人:Roland M Tisch
-
依托单位:
海外基金