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

• 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
• 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

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.

摘要 THEMIS与越来越多的人类炎症性疾病有关，包括乳糜泻， 多发性硬化症和特应性皮炎。THEMIS相关疾病影响不同的解剖部位， 遵循不同的发病机制，将THEMIS作为核心“炎症”控制器之一。尽管大力 THEMIS与人类多种炎性疾病和T细胞严重缺陷的相关性 THEMIS缺陷小鼠的发育和选择，THEMIS的功能及其途径或因子， 与保持神秘的互动。THEMIS 1在T细胞中表达，在那里它作为下游的关键衔接子发挥作用。 的TCR。在胸腺细胞中，它对于导致幼稚T细胞产生的阳性选择至关重要。Themis 在成熟的CD8ab和CD4 TCRab T细胞中继续表达，但其在成熟T细胞中的作用尚不清楚。 此外，THEMIS在细胞核中以及在细胞质中表达，并且尽管THEMIS作为TCR， 适配器，已经得到了很好的研究，它在细胞核中的作用仍然不确定， 这种差异性亚细胞定位对于其在胸腺细胞或成熟T细胞中的功能的重要性。这些 我们对THEMIS生物学的理解存在重大差距，这极大地阻碍了识别THEMIS的进展。 THEMIS在这些疾病中的作用，它是相关的，或设计有效的策略，以靶向THEMIS， 治疗炎性疾病或增强对感染和癌症的保护。这里的提议 通过使用独特的新工具来检查细胞质中的THEMIS， 以及未成熟和成熟T细胞的细胞核。