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

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种独特属性，它提供了对病原体极其有效的防御。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）可以有效地根除威胁生命的病原体，特别是过去曾经遇到过的或已接种过疫苗的病毒。因此，免疫记忆对于维持健康和长寿至关重要，控制免疫记忆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一种手段。然而，目前尚不清楚免疫记忆是如何在免疫系统中被决定和维持的。本研究旨在揭示淋巴细胞，特别是T细胞如何提供免疫记忆。T细胞协调其他免疫细胞的活动，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以T细胞为目标，从而引起获得性免疫缺陷综合征（艾滋病）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，我们将采用免疫学、分子生物学、基因组学和系统生物学的综合方法，并在基因水平上研究免疫记忆如何在记忆T细胞中维持。免疫学和分子方法将确定哪些已知分子参与记忆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。系统方法将识别分子之间复杂的调节机制，从而为充分发现记忆T细胞的产生和功能机制提供严格的框架。这些结合在一起将揭示T细胞记忆的关键机制，然后可以用于开发新的免疫抑制药物和疫苗设计。该项目旨在迅速将知识和技术转移到工业，包括制药工业。在基因水平上理解T细胞记忆的机制不仅对科学进步很重要，而且对开放和开发新的免疫抑制药物和疫苗也很重要。我们的目标是利用该项目的研究结果来提高新药开发筛选过程的效率。本研究采用实验与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性价比。这项研究是高度多学科的。申请人是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，申请人将与数学建模师、统计学家和免疫学家协调合作，为这个问题提供最有效的答案。这项研究的结果将有益于广泛的科学界，并有助于人类和动物的健康和福祉。此外，该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。

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.