Uncovering the hidden universe of metabolite-specific T lymphocytes,using human multiorgan microphysiological systems.

利用人体多器官微生理系统揭示代谢物特异性 T 淋巴细胞的隐藏宇宙。

• 批准号: 10652631
• 负责人: Martin Trapecar
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652631
• 关键词: Affect; Antigens; Area; Autoimmune; Autoimmune Diseases; Autoimmune Hepatitis; Basic Science; Behavior; Biological; Cells; Circulation; Complex; Development; Disease; Goals; Heterogeneity; Homeostasis; Human; Immune; Inflammatory; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Knowledge; Liver; Lymphocyte; Metabolic; Metabolic Diseases; Modeling; Molecular; Mucous Membrane; Multiple Sclerosis; Neurodegenerative Disorders; Organ; Pathology; Physiology; Public Health; Research Project Grants; Resolution; Role; Shapes; Systems Biology; T-Lymphocyte; Tissue Donors; Tissues; Ulcerative Colitis; body system; computerized tools; disorder prevention; gut-liver axis; human model; insight; microbial; microphysiology system; multiple omics; receptor; tool

PROJECT SUMMARY Metabolic and inflammatory disorders such as autoimmune and neurodegenerative diseases are increasing at alarming rates. Many of these are not tissue-specific occurrences but complex and often overlapping pathologies of unknown origin for which no cure exists. Examples are concurring pathologies of the gut-liver axis, such as inflammatory bowel disease and inflammatory pathologies of the liver. The discovery of “unconventional” T lymphocytes and their ability to respond to non-peptide antigens, marks a new area in the exploration of how migratory cells and immunometabolic networks shape the emergence of autoimmune and metabolic diseases. These are comprised of a heterogeneous group of lymphocytes, such as mucosa-associated invariant T cells, whose invariant TCR can recognize cellular and microbial metabolites via presentation through the MHC-like receptor 1 (MR1). Emerging evidence suggest MR1-restricted T cells to be implicated in a wide variety of disorders ranging from ulcerative colitis to type 1 diabetes, autoimmune hepatitis and multiple sclerosis via TCR-specific and non-specific means. However, lack of models relevant to human physiology represents a significant hurdle in our understanding of how MR1-restricted T cells affect the host and diseases. We have developed an approach that utilizes multiorgan human microphysiological models (MOMPS) of donor-matched tissues and unbiased systems biology tools to gain granular insight into causal relationships between cellular crosstalk and immunometabolic illnesses. In order to gain critical knowledge about the heterogeneity and functionality of MR1-restricted lymphocytes, we will combine single-cell characterization of human MR1-restricted T cells across donor-matched tissues and circulation, with mechanistic studies in a microphysiological model of the gut-liver axis. These MOMPS will be used to systematically search for causal relationships between MR1-restricted lymphocytes, tissues, and external factors by reconstructing donor tissue at various levels of complexity. Each level will be challenged via predetermined inflammatory and metabolic perturbations. Multiomic observation of changes based on interaction and perturbation at each degree of complexity will allow us to construct interaction networks that reveal causal relationships among entities. With computational tools and resolution into molecular underpinnings of cellular and tissue homeostasis, MOMPS represent a unique opportunity to systematically dissect how interactions at a lower order inform new behavior at the macro scale within and between organ systems. While the gut-liver axis will serve as a model in this proposal, the developed approach, together with fundamental biological insights into MR1 expression by parenchymal tissue and function of MR1-restricted T cells, will be applicable to other organ systems and a variety of pathologies. Our overarching goal is to identify tangible targets and new cell-based approaches to modulate autoimmune pathologies but also contribute new tools that shed light on the fundamental origins of complex diseases.

项目总结 代谢和炎症性疾病，如自身免疫性疾病和神经退行性疾病，在 惊人的速度。其中许多不是特定于组织的发生，而是复杂且经常重叠的 无法治愈的不明原因的病理。例如，肠道和肝脏的共同病理。 轴心，如炎症性肠病和肝脏炎性病理。 “非常规”T淋巴细胞的发现及其对非肽抗原的反应能力，标志着 在探索迁移细胞和免疫代谢网络如何塑造 自身免疫性和代谢性疾病。这些细胞由一组不同种类的淋巴细胞组成，例如 粘膜相关不变T细胞，其不变TCR可识别细胞和微生物代谢产物 通过MHC样受体1(MR1)递呈。新的证据表明，MR1限制的T细胞 与多种疾病有关，从溃疡性结肠炎到1型糖尿病、自身免疫性肝炎 和多发性硬化症通过TCR特异性和非特异性手段。 然而，缺乏与人类生理学相关的模型是我们理解 MR1限制性T细胞如何影响宿主和疾病。我们已经开发出一种利用多器官 捐献者匹配组织的人类微生理模型(MOMP)和无偏系统生物学工具 深入了解细胞串扰和免疫代谢疾病之间的因果关系。按顺序 为了获得有关MR1限制性淋巴细胞的异质性和功能的关键知识，我们将 结合供者匹配组织和供者组织中人类MR1限制性T细胞的单细胞特征 循环，以及肠道-肝轴的微生理模型的机制研究。这些MOMP将是 用于系统地搜索受MR1限制的淋巴细胞、组织和 外部因素通过重建不同复杂程度的供体组织来实现。每个级别将通过以下方式进行挑战 预先确定的炎症和代谢紊乱。基于交互的变化的多组学观察 在每种复杂程度上的扰动将允许我们构建揭示因果关系的交互网络 实体之间的关系。通过计算工具和对细胞的分子基础的解析 和组织动态平衡，MOMPS代表着一个独特的机会，可以系统地剖析 较低的级别在器官系统内和器官系统之间的宏观尺度上通知新的行为。而肠道-肝脏轴 将作为这项提案的模型，所开发的方法，以及对 MR1在实质组织中的表达和MR1限制性T细胞的功能，将适用于其他器官 系统和各种病理。我们的首要目标是确定切实的目标和新的基于细胞的 调节自身免疫病理的方法，但也有助于提供新的工具，揭示 复杂疾病的根本起源。