High-dimensional mass imaging of muscle for the mechanistic study of T cells in inclusion body myositis

肌肉高维质量成像用于 T 细胞在包涵体肌炎机制研究中的应用

• 批准号: 10669370
• 负责人: Sergio Armando Villalta
• 金额: $ 27.63万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669370
• 关键词: Ablation; Address; Affect; Age; Apoptosis; Autoimmunity; Biological Assay; Biopsy Specimen; Blood; Blood specimen; CD8-Positive T-Lymphocytes; CD8B1 gene; CDKN1A gene; CDKN2A gene; Cardiovascular system; Cell Aging; Cell Death; Cell physiology; Cells; Cessation of life; Characteristics; Circulation; Clinical; Clinical Trials; Clinical Trials Design; Clonal Expansion; Cytometry; Data; Development; Disease; Disease Progression; Etiology; Exhibits; Flow Cytometry; Foundations; Frequencies; Funding; Future; Goals; Granzyme; Image; Immune response; Immune system; Immunotherapy; In Vitro; Inclusion Body Myositis; Inflammatory; Interferon Type II; Investigation; Knowledge; Measures; Molecular; Muscle; Muscle Cells; Muscle Weakness; Myopathy; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Natural History; Nature; Neurology; Outcome; Parents; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Prevalence; Production; Proteins; Rare Diseases; Refractory; Reporting; Research; Resistance; Resolution; Role; Severities; Severity of illness; Skeletal Muscle; Sporadic Inclusion Body Myopathy; T cell differentiation; T cell regulation; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; United States; United States National Institutes of Health; Work; age related; beta-Galactosidase; disability; efficacy testing; high dimensionality; illness length; imaging platform; innovation; insight; novel marker; novel strategies; novel therapeutic intervention; novel therapeutics; patient stratification; perforin; pharmacologic; senescence; tool

PROJECT SUMMARY/ABSTRACT Sporadic inclusion body myositis (IBM) is a rare, acquired muscle disease of unknown etiology. Our long-term goal is to define how T cells contribute to the pathogenesis of IBM. T cells undergo clonal expansion and differentiation but lose their proliferative capacity and exhibit characteristics of senescence, including production of cytolytic proteins (e.g. perforin and granzyme) that promote muscle cell death. Further, senescent T cells are resistance to apoptosis, which may explain the treatment refractory nature of IBM. The objective of the current study is to define molecular attributes of senescence in highly-differentiated T cells, and correlate these features with clinical measures of IBM. Further, a pharmacological approach will be used to define the mechanism regulating T cell senescence in IBM. We will test the central hypothesis that senescent muscle T cells promote the severity and progression of IBM. In preliminary studies, we show that the frequency of KRLG1+CD8+ senescent-like T cells was elevated in the blood of IBM patients. Although KRLG1+CD8+ T cells correlated with disease duration, they did not correlate with the severity of IBM. Given that an immune response can vastly differ between blood and the affected tissue, mechanistic studies with high-resolution profiling of the immune response in IBM muscle are needed to determine relationships between senescent T cells and IBM. The central hypothesis of this investigation will be tested by addressing two specific aims. In specific aim 1, we will define the molecular features of senescent muscle T cells and their relationship to disease severity and progression. The lack of tools to rigorously phenotype T cell populations in muscle has made it difficult to study these cells and determine their function in IBM. Thus, an innovative high-dimensional mass imaging platform will be used to address this limitation, and determine the relationship between senescent T cells and IBM. In specific aim 2, we will determine the ability of senolytic therapy to ablate senescent CD8+ T cells, which will provide mechanistic insight on the regulation of T cell senescence during IBM. The proposed study is significant as it will establish a foundation for defining the function of dysregulated T cell responses in IBM. Further, it will provide preliminary evidence to support the testing of a novel therapeutic approach for this disease. The proposed research is also innovative as it uses cutting-edge advancements in mass imaging to rigorously interrogate the senescent phenotype of T cells in IBM. The use of senolytic drugs also marks an innovative approach for targeting dysfunctional T cells and defining the role of senescent T cells in IBM. Collectively, the proposed work promises to advance our understanding of the role of the immune system in the pathogenesis of IBM, and may have a broad impact by guiding the development of novel strategies to treat and/or cure IBM.

项目概要/摘要 散发性包涵体肌炎 (IBM) 是一种罕见的、病因不明的获得性肌肉疾病。我们的长期 目标是确定 T 细胞如何促进 IBM 的发病机制。 T 细胞进行克隆扩增并 分化但失去增殖能力并表现出衰老特征，包括生产 促进肌肉细胞死亡的溶细胞蛋白（例如穿孔素和颗粒酶）。此外，衰老的T细胞 对细胞凋亡的抵抗，这可能解释了 IBM 治疗难治性的本质。当前的目标 研究的目的是定义高度分化 T 细胞衰老的分子属性，并将这些特征关联起来 与IBM的临床测量。此外，将使用药理学方法来定义其机制 调节 IBM 中的 T 细胞衰老。我们将检验衰老肌肉 T 细胞促进衰老的中心假设 IBM 的严重性和进展。在初步研究中，我们表明 KRLG1+CD8+ 的频率 IBM 患者血液中的衰老样 T 细胞含量升高。尽管 KRLG1+CD8+T 细胞与 疾病持续时间，它们与 IBM 的严重程度无关。鉴于免疫反应可能存在很大差异 血液和受影响组织之间的机制研究以及免疫反应的高分辨率分析 需要确定 IBM 肌肉中衰老 T 细胞和 IBM 之间的关系。中心假设 这项调查的进展将通过解决两个具体目标来进行检验。在具体目标 1 中，我们将定义分子 衰老肌肉 T 细胞的特征及其与疾病严重程度和进展的关系。缺乏工具 对肌肉中 T 细胞群进行严格的表型分析使得研究这些细胞并确定它们的 IBM 中的功能。因此，创新的高维质量成像平台将用于解决这个问题 局限性，并确定衰老 T 细胞与 IBM 之间的关系。在具体目标2中，我们将 确定 senolytic 疗法消除衰老 CD8+ T 细胞的能力，这将提供机制见解 IBM 期间 T 细胞衰老的调控。拟议的研究意义重大，因为它将建立一个 定义 IBM 中失调的 T 细胞反应功能的基础。此外，还将提供初步 支持测试这种疾病的新治疗方法的证据。拟议的研究是 同样具有创新性，因为它利用大规模成像领域的尖端技术来严格审视衰老细胞 IBM 中 T 细胞的表型。 senolytic 药物的使用也标志着一种靶向治疗的创新方法 功能失调的 T 细胞并定义了 IBM 中衰老 T 细胞的作用。总的来说，拟议的工作承诺 促进我们对免疫系统在 IBM 发病机制中的作用的理解，并且可能具有 通过指导治疗和/或治愈 IBM 的新策略的开发来产生广泛的影响。