Elucidation of the transcriptional programme of memory T cells by a systems approach

通过系统方法阐明记忆 T 细胞的转录程序

• 批准号: BB/J013951/1
• 负责人: Masahiro Ono
• 金额: $ 170.12万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ013951%2F1
• 关键词: Elucidation; transcriptional; programme; memory; cells

This project aims to reveal the fundamental molecular mechanisms of immunological memory at the gene level. Immunological memory is a unique attribute of the adaptive immune system and provides extremely efficient defense against pathogens. Because the immune system has this capacity, humans and animals (including mammals, birds, and fish) can efficiently eradicate life-threatening pathogens, especially viruses, that were once encountered in the past or for which they were immunised. Thus, immunological memory is essential for maintaining health and longevity, and the control of immunological memory will provide a mean for improving the prevention and treatment of infectious diseases, and for developing effective vaccines against pathogens such as HIV. It is, however, still unclear how immunological memory is determined and maintained in the immune system. This study aims to reveal how immunological memory is provided by lymphocytes, especially in T cells. T cells coordinate the activities of other immune cells, and generate efficient and rapid responses to pathogens. Thus, not surprisingly, some viruses such as HIV target T cells, and thereby cause the major symptoms of acquired immune deficiency syndrome (AIDS). Memory T cells may play central roles both in immunity to pathogens and on vaccination. Research on memory T cells, however, has been difficult and will require multiple approaches, including immunology, molecular biology, and systems biology.Thus, we will employ an integrated approach of immunology, molecular biology, genomics, and systems biology, and address how immunological memory is maintained in memory T cells at the gene level. Immunological and molecular approaches will identify which of already known molecules are involved in generation and function of memory T cells. Genomics will identify new molecular mechanisms for controlling memory T cells. The systems approach will identify the complex regulatory mechanisms between the molecules and thereby provide rigid frameworks to fully discover the mechanisms of the generation and function of memory T cells. These together will reveal the critical mechanisms that underlie T cell memory, which can then be exploited for the development of new immunosuppressive drugs and vaccine designs. The project is designed to swiftly transfer knowledge and technology to industry, including the pharmaceutical industry. The understanding of the mechanism of T cell memory at the gene level is important not only for scientific progress but also for patency and for the development of new immunosuppressive drugs and vaccines. We also aim to use the findings of the project to improve the efficiency of the screening processes in the development of new drugs. The combined approach of experiments and mathematical modelling in this study can be directly used for screening processes for immunomodulative drugs, which can contribute to improve the cost performance of drug development at the preclinical stage.This study is highly multidisciplinary. The applicant is an immunologist and molecular biologist, and has recently trained for genomics and systems biology. With this background, the applicant will coordinate collaborations with mathematical modellers, statisticians, and immunologists to provide the most efficient answers to this problem. The findings of this study will benefit broad scientific communities and contribute to health and well-being of humans and animals. In addition, this study will provide novel frameworks for systems biology, which can be used in many biological areas.

本项目旨在从基因水平揭示免疫记忆的基本分子机制。免疫记忆是适应性免疫系统的一个独特属性，对病原体提供了极其有效的防御。由于免疫系统具有这种能力，人类和动物(包括哺乳动物、鸟类和鱼类)可以有效地根除过去曾遇到或接种过疫苗的威胁生命的病原体，特别是病毒。因此，免疫记忆对于保持健康和长寿至关重要，而免疫记忆的控制将为改进传染病的预防和治疗以及开发针对艾滋病毒等病原体的有效疫苗提供手段。然而，目前仍不清楚免疫记忆是如何在免疫系统中确定和维持的。这项研究旨在揭示淋巴细胞，特别是T细胞是如何提供免疫记忆的。T细胞协调其他免疫细胞的活动，并对病原体产生有效和快速的反应。因此，毫不奇怪，一些病毒，如艾滋病毒，攻击T细胞，从而导致获得性免疫缺陷综合征(AIDS)的主要症状。记忆T细胞可能在对病原体的免疫和疫苗接种中发挥核心作用。然而，记忆T细胞的研究一直很困难，需要多种方法，包括免疫学、分子生物学和系统生物学，因此，我们将综合运用免疫学、分子生物学、基因组学和系统生物学的方法，从基因水平探讨记忆T细胞如何维持免疫记忆。免疫学和分子方法将确定哪些已知的分子参与记忆T细胞的产生和功能。基因组学将确定控制记忆T细胞的新分子机制。系统的方法将识别分子之间的复杂调控机制，从而提供严格的框架，以全面发现记忆T细胞的产生和功能的机制。这些都将揭示T细胞记忆的关键机制，然后可以利用这些机制来开发新的免疫抑制药物和疫苗设计。该项目旨在将知识和技术迅速转移到包括制药行业在内的行业。在基因水平上了解T细胞记忆的机制，不仅对于科学进步，而且对于开放和开发新的免疫抑制药物和疫苗都是重要的。我们的目标也是利用该项目的结果来提高新药开发中筛选过程的效率。本研究采用实验和数学建模相结合的方法，可直接用于免疫调节药物的筛选过程，有助于提高临床前阶段药物开发的成本效益。申请者是一名免疫学家和分子生物学家，最近接受了基因组学和系统生物学的培训。在此背景下，申请者将协调与数学建模人员、统计学家和免疫学家的合作，为这个问题提供最有效的答案。这项研究的结果将使广泛的科学界受益，并为人类和动物的健康和福祉做出贡献。此外，这项研究将为系统生物学提供新的框架，可用于许多生物学领域。

项目成果

A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo.

• DOI: 10.1083/jcb.201711048
• 发表时间: 2018-08-06
• 期刊: The Journal of cell biology
• 作者: Bending D;Prieto Martín P;Paduraru A;Ducker C;Marzaganov E;Laviron M;Kitano S;Miyachi H;Crompton T;Ono M
• 通讯作者: Ono M

A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme

时间动态 Foxp3 自动调节转录电路控制效应 Treg 程序

• DOI: 10.1101/238386
• 发表时间: 2018
• 作者: Bending D

A Timer for analyzing temporally dynamic changes in transcription during differentiation in vivo

用于分析体内分化过程中转录的时间动态变化的计时器

• DOI: 10.1101/217687
• 发表时间: 2017
• 作者: Bending D

A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme.

• DOI: 10.15252/embj.201899013
• 发表时间: 2018-08-15
• 期刊: The EMBO journal
• 作者: Bending D;Paduraru A;Ducker CB;Prieto Martín P;Crompton T;Ono M
• 通讯作者: Ono M

255 Foxp3 activation within effector T-cells controls the antigen-specific T-cell response in the contact hypersensitivity model

255 效应 T 细胞内的 Foxp3 激活控制接触超敏反应模型中的抗原特异性 T 细胞反应

• DOI: 10.1016/j.jid.2016.06.275
• 发表时间: 2016
• 期刊: Journal of Investigative Dermatology
• 影响因子: 6.5
• 作者: Bending D