Understanding the regulation of IL-17 producing lymphocytes by the cytokine TGF (beta).

了解细胞因子 TGF (β) 对产生 IL-17 的淋巴细胞的调节。

• 批准号: 2628136
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2628136
• 关键词: Understanding; regulation; IL; 17; producing

Th17 cells are a lineage of CD4+T-helper cells that have been shown to be critical mediators of immunity at barrier surfaces such as the gastrointestinal tract and skin. At these sites these T-helper cells participate in both immune surveillance and maintenance of barrier integrity and therefore mediate protection against both bacterial and fungal infections. However, Th17 cells have also been shown to promote aberrant inflammation and are key drivers of pathology in a plethora of auto-inflammatory conditions, including multiple sclerosis, rheumatoid arthritis, and periodontitis (the latter a particular focus in the lab). Understanding these positive and negative roles for Th17 cells has been the aim of much research and it is becoming increasingly clear that Th17 cells exhibit both extensive functional diversity and plasticity. Indeed, recent studies have identified gene signatures that distinguish "pathogenic" Th17 cells, which drive tissue inflammation and damage, from barrier protective "homeostatic" Th17 cells. However, the extracellular signals that drive acquisition of these disparate fates and functions of Th17 cells remain poorly understood, but would herald an important advance allowing the selective inhibition of pathogenic Th17 cells to become a therapeutic reality. The aim of this project is to mechanistically understand how Th17 cells integrate local signals to be trained to take on "homeostatic" and "pathogenic" functions. This project will employ sophisticated transgenic mouse models, alongside examination of Th17 cells from human tissue samples, to generate unprecedented insight into how Th17 cells acquire distinct functional capabilities. By operating across immunology, molecular biology, bioinformatics and translational medicine fields the student will gain vital understanding of the value of interdisciplinary approaches and be trained in cutting-edge immunology techniques including: in vivo models of inflammation, in vitro culture of immune cells, multicolour flow-cytometry, and genome-wide transcriptional profiling. Ultimately, this project aims to inform development of novel therapeutics to that will allow precise manipulation of Th17 cells. Moreover, data generated will improve our current understanding of Th17 cell biology, providing insight into the plethora of disorders in which aberrant Th17 cell function is implicated.

Th17细胞是CD4+ t辅助细胞的一个谱系，已被证明是胃肠道和皮肤等屏障表面免疫的关键介质。在这些部位，这些辅助性t细胞参与免疫监视和维持屏障完整性，因此介导对细菌和真菌感染的保护。然而，Th17细胞也被证明可以促进异常炎症，并且是多种自身炎症疾病的关键驱动因素，包括多发性硬化症、类风湿性关节炎和牙周炎（后者是实验室的重点）。了解Th17细胞的这些积极和消极作用已成为许多研究的目标，并且越来越清楚Th17细胞具有广泛的功能多样性和可塑性。事实上，最近的研究已经确定了区分“致病”Th17细胞和屏障保护“稳态”Th17细胞的基因特征。Th17细胞驱动组织炎症和损伤。然而，驱动Th17细胞获得这些不同命运和功能的细胞外信号仍然知之甚少，但这将预示着一项重要的进展，使选择性抑制致病性Th17细胞成为治疗现实。该项目的目的是从机制上理解Th17细胞如何整合局部信号以接受“稳态”和“致病”功能的训练。该项目将采用复杂的转基因小鼠模型，同时检查来自人体组织样本的Th17细胞，以对Th17细胞如何获得独特的功能能力产生前所未有的见解。通过在免疫学，分子生物学，生物信息学和转化医学领域的操作，学生将获得跨学科方法价值的重要理解，并接受尖端免疫学技术的培训，包括：体内炎症模型，免疫细胞体外培养，多色流式细胞术和全基因组转录分析。最终，这个项目旨在为开发新的治疗方法提供信息，从而可以精确地操纵Th17细胞。此外，生成的数据将提高我们目前对Th17细胞生物学的理解，为涉及异常Th17细胞功能的过多疾病提供见解。