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The role of AIM2 in T cell-mediated autoimmunity

AIM2 在 T 细胞介导的自身免疫中的作用

基本信息

批准号：
10321613
负责人：
Roland M Tisch
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-05 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321613
关键词：
AIM2 gene AKT Signaling Pathway Affect Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving Binding CD4 Positive T Lymphocytes Cell Compartmentation Cell Death Cell physiology Cells Cellular immunotherapy Complex DNA DNA-dependent protein kinase Defect Dendritic Cells Development Diabetes Mellitus Eragrostis Event Exhibits Foundations Goals Homeostasis Host Defense Human Hypersensitivity Immune Immunotherapy Inbred NOD Mice Inflammasome Inflammation Insulin-Dependent Diabetes Mellitus Interleukin-18 Malignant Neoplasms Mediating Mediator of activation protein Mind Modeling Natural Immunity PI3K/AKT Pathogenicity Pathway interactions Peripheral Phenotype Phosphorylation Production Property Proto-Oncogene Proteins c-akt Regulation Role Self Tolerance Signal Pathway Signal Transduction Stimulus T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Thymic epithelial cell Thymus Gland Tissues Work base central tolerance diabetogenic ds-DNA immunoregulation insight negative affect novel pathogen pathogenic microbe peripheral tolerance prevent response sensor

项目摘要

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.

总结/摘要 T细胞介导的自身免疫性疾病如1型糖尿病（T1 D）是由于复杂的事件导致的，中枢和外周耐受性失调。确定调节自我耐受性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并治疗T1 D和其他T细胞介导的自身免疫性疾病。本申请基于我们的新观察，即AIM 2炎性小体缺陷的NOD小鼠分子保持无糖尿病。AIM 2是一种参与宿主防御的细胞质免疫传感器。结合后 AIM 2是一种来自微生物病原体的双链DNA，它组装成一种炎性复合体，促炎性细胞因子IL-1bβ和IL-18的产生，以及细胞凋亡介导的细胞死亡。最近的研究，然而，已经证明AIM 2可以在宿主防御之外通过免疫调节来发挥调节功能。非锥形途径，独立于炎性小体激活。在这里，AIM 2起着消极的作用。 PI 3 K/AKT信号通路中的激酶DNA-MAPK的调节剂。我们发现，AIM 2-β 1缺陷型NOD小鼠中糖尿病的缺乏也独立于炎性小体激活。此外，有证据表明，在AIM 2-β 1缺陷NOD小鼠中，Bβ细胞自身免疫被多种免疫抑制剂阻断。胸腺抗原呈递细胞、外周树突状细胞功能和T细胞亚群的影响机制分化我们推测AIM 2在调节PI 3 K/DNA-PKK/AKT-PKK过程中起着关键的检查点作用依赖性刺激和细胞成熟/分化，其影响自身免疫耐受和糖尿病发生。反应我们的目标是确定AIM 2调节自我耐受性的关键机制。考虑到这一点，具体目标1将侧重于AIM 2对胸腺髓质上皮细胞刺激功能的影响，胸腺树突细胞特异性Aim 2将定义AIM 2在调节树突状细胞促炎中的作用与致耐受性功能相比。最后，具体目标3将研究AIM 2如何控制致病性T细胞亚群分化。预计这项工作将有助于深入了解新的机制，调节中枢和外周自我耐受的途径，以及靶向 AIM 2通路用于治疗目的。