Determining important novel mechanisms that regulate T-cell-mediated immune responses.

确定调节 T 细胞介导的免疫反应的重要新机制。

• 批准号: 1908755
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1908755
• 关键词: Determining; important; novel; mechanisms; regulate

The immune system must be capable of rapidly responding to pathogens, but be tightly regulated to prevent self-harmful immune responses against our own tissues to maintain health. T-cells are crucial immune cells that fight a variety of pathogens, but are can become activated to attack our own bodies and disrupt homoeostasis. Thus, identifying important mechanisms that regulate T-cells is crucial in understanding how the immune system is regulated to promote health.Recent work in the Travis lab has identified a crucial molecule, expressed by antigen presenting dendritic cells (DCs) and immunosuppressive regulatory T-cells (Tregs) that is vital in regulation of T-cell responses. Thus, expression of the cell surface receptor integrin alphav beta8 by both DCs and Tregs is fundamental in promoting T-cell health 1-3, with expression of the integrin by DCs important in regulating responses to infection. Thus, how integrin alphav beta8 is regulated, and the molecular pathways downstream of the integrin that are important in controlling immune cell behaviour and T-cell responses are crucial, but unanswered, questions.Using the bioinformatics expertise of Schwartz, publicly available microarray datasets (www.immgen.com) will be interrogated to identify gene networks that are significantly correlated with expression of integrin alphav beta8. The functional importance of candidate genes identified from the bioinformatics screen will then be tested using a variety of in vitro and in vivo immunological assays in mice (Travis), using knockout mouse models and/or CRISPR-mediated knockdown of targets of interest in primary cells. Initial focus of experiments will be on effects on T-cell responses shown to be regulated by integrin aphav beta8 (i.e. induction of suppressive Tregs, inhibition of Th2 responses, induction of Th17 responses). Interesting findings in mice will then be translated into humans, looking at candidate gene function by CRISPR-mediated knockdown in primary human immune cells from healthy individuals and patients with inflammation. Thus, the project will provide a unique training opportunity combining computational biology and immunology, identifying crucial mechanisms that are important in T-cell responses keeping us healthy. The specific aims of the project are to:1. Determine gene signatures/pathways that are significantly associated with expression of integrin alphav beta8, via bioinformatic modelling of extensive publicly available microarray data for immune cells. 2: Determine the functional importance of associated gene pathways in regulation of T-cell responses using murine models 3: Determine the functional importance of genes identified in aims 1 and 2 in primary human immune cells. The project brings together experts in immune cell biology (Travis) and bioinformatics (Schwartz), to determine novel pathways by which T cell responses are controlled. The project will provide important training in both computational biology, and how hypotheses generated from bioinformatics can be directly tested experimentally. The project will therefore directly address the BBSRC's goal for researchers to be able to apply computational techniques to biological data. Such skills will put the student in an extremely strong position after their PhD, given the massive expansion in big genomic and proteomic datasets that are currently underutilised by general biologists due to their difficulty to navigate for people without bioinformatics training.

免疫系统必须能够迅速对病原体作出反应，但要严格调节，以防止对我们自己的组织产生有害的免疫反应，以维持健康。t细胞是对抗多种病原体的关键免疫细胞，但它们也会被激活来攻击我们自己的身体，破坏体内的平衡。因此，确定调节t细胞的重要机制对于理解如何调节免疫系统以促进健康至关重要。Travis实验室最近的工作已经确定了一个关键分子，由抗原呈递树突状细胞（dc）和免疫抑制调节性t细胞（Tregs）表达，在t细胞反应的调节中至关重要。因此，dc和Tregs表达细胞表面受体整合素alphav β 8是促进t细胞健康的基础1-3，dc表达整合素在调节感染反应中很重要。因此，如何调节整合素α - β 8，以及整合素下游的分子途径在控制免疫细胞行为和t细胞反应中是重要的，这些都是至关重要的，但没有答案的问题。利用施瓦茨的生物信息学专业知识，公开可用的微阵列数据集（www.immgen.com）将被询问，以确定与整合素alphav β 8表达显著相关的基因网络。从生物信息学筛选中鉴定出的候选基因的功能重要性将在小鼠（Travis）中使用各种体外和体内免疫分析进行测试，使用敲除小鼠模型和/或crispr介导的原代细胞中感兴趣的靶标敲除。实验的最初重点将放在整合素aphav β 8对t细胞反应的影响上（即诱导抑制性Tregs，抑制Th2反应，诱导Th17反应）。然后，在小鼠身上的有趣发现将被转化到人类身上，通过crispr介导的敲除来自健康个体和炎症患者的初级人类免疫细胞来观察候选基因的功能。因此，该项目将提供一个独特的培训机会，结合计算生物学和免疫学，确定在t细胞反应中保持我们健康的重要机制。该项目的具体目标是：1。通过广泛公开的免疫细胞微阵列数据的生物信息学建模，确定与整合素α β 8表达显著相关的基因特征/途径。2 .利用小鼠模型确定相关基因通路在调节t细胞反应中的功能重要性3 .确定目的1和2中鉴定的基因在原代人免疫细胞中的功能重要性。该项目汇集了免疫细胞生物学（Travis）和生物信息学（Schwartz）的专家，以确定控制T细胞反应的新途径。该项目将提供计算生物学方面的重要培训，以及如何通过实验直接测试生物信息学产生的假设。因此，该项目将直接解决BBSRC的目标，即研究人员能够将计算技术应用于生物数据。这些技能将使学生在获得博士学位后处于极其有利的地位，因为大型基因组和蛋白质组学数据集的大规模扩展目前尚未被普通生物学家充分利用，因为这些数据集难以为没有受过生物信息学培训的人导航。