The Role of Cytoplasmic and Nuclear THEMIS in Immature and Mature T cells

细胞质和细胞核 THEMIS 在未成熟和成熟 T 细胞中的作用

基本信息

批准号：
10552636
负责人：
HILDE MC CHEROUTRE
金额：
$ 68.84万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
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：
2020-02-14 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552636
关键词：
Address Affect Anatomy Atopic Dermatitis Autoimmune Diseases Automobile Driving Binding Binding Sites Biology CRISPR/Cas technology Celiac Disease Cell Nucleus Cellular biology Chromatin Cytoplasm DNA Footprint Data Defect Development Disease Dominant-Negative Mutation EGF gene Evaluation Event Generations Government Homeostasis Human Immune response Impairment Infection Inflammatory Insulin-Like Growth Factor I Knockout Mice MAPK1 gene Malignant Neoplasms Mature T-Lymphocyte Mediating Memory Mouse Strains Multiple Sclerosis Mus Mutant Strains Mice Mutate Nuclear Nuclear Export Pathogenesis Pathology Pathway interactions Persons Phenotype Play Proteins Regulation Risk Role Signal Pathway Signal Transduction Signaling Molecule T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymocyte Development Thymus Gland Transgenes conditional knockout design experimental study loss of function mutant pathogen thymocyte tool transcriptome

项目摘要

Abstract THEMIS associates with a growing number of inflammatory diseases in humans, including Celiac Disease, Multiple Sclerosis and Atopic Dermatitis. THEMIS associated disorders affect different anatomical sites and follow different pathogeneses, placing THEMIS as one of the core “inflammatory”-controllers. Despite the strong association of THEMIS with multiple inflammatory diseases in humans and the profound defects in T cell development and selection in THEMIS-deficient mice, the function of THEMIS and the pathways or factors it interacts with remain enigmatic. THEMIS1 is expressed in T cells where it functions as a key adaptor downstream of the TCR. In thymocytes it is essential for positive selection leading to the generation of naïve T cells. THEMIS continues to be expressed in mature CD8ab and CD4 TCRab T cells but its role in mature T cells is not known. Moreover, THEMIS is expressed in the nucleus as well as in the cytoplasm and although THEMIS, as a TCR adaptor, has been well studied, it’s role in the nucleus remains undefined and nothing is known about the significance of this differential subcellular localization for its function in thymocytes or mature T cells. These significant gaps in our understanding of the biology of THEMIS greatly impede on the progress to identify the role of THEMIS in those diseases it is associated with or to design effective strategies to target THEMIS for the treatment of inflammatory diseases or to enhance protection against infections and cancers. The proposal here sets out to address these significant gaps with the use of unique new tools to examine THEMIS in the cytoplasm and nucleus of immature and mature T cells.

抽象的 THEMIS 与人类越来越多的炎症性疾病有关，包括乳糜泻、多发性硬化症和特应性皮炎相关疾病影响不同的解剖部位和遵循不同的发病机制，尽管 THEMIS 具有很强的作用，但它还是核心“炎症”控制剂之一。 THEMIS 与人类多种炎症性疾病的关联以及 T 细胞的严重缺陷 THEMIS 缺陷小鼠的发育和选择、THEMIS 的功能及其途径或因素 THEMIS1 与 T 细胞中的相互作用仍然是个谜。在胸腺细胞中，它对于导致初始 T 细胞的产生至关重要。继续在成熟 CD8ab 和 CD4 TCRab T 细胞中表达，但其在成熟 T 细胞中的作用尚不清楚。此外，THEMIS 在细胞核和细胞质中表达，尽管 THEMIS 作为 TCR 适配器，已被充分研究，它在细胞核中的作用仍然不确定，并且对它一无所知这种差异性亚细胞定位对其在胸腺细胞或成熟 T 细胞中的功能的重要性。我们对 THEMIS 生物学的理解存在重大差距，极大地阻碍了确定其相关性的进展。 THEMIS 在与其相关的疾病中的作用或设计有效的策略来针对 THEMIS 治疗炎症性疾病或增强对感染和癌症的保护。着手通过使用独特的新工具来检查细胞质中的 THEMIS 来解决这些重大差距以及未成熟和成熟T细胞的细胞核。