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.

项目摘要/摘要 散发性包容体肌炎（IBM）是一种罕见的，可获得的肌肉疾病，是未知的病因。我们的长期 目标是定义T细胞如何促进IBM的发病机理。 T细胞经历克隆膨胀和 分化但失去了它们的增殖能力和衰老的特征，包括生产 促进肌肉细胞死亡的细胞溶解蛋白（例如培养蛋白和颗粒酶）此外，衰老的T细胞是 对细胞凋亡的抗性，这可以解释IBM的治疗难治性。电流的目的 研究是定义高分差异T细胞中衰老的分子属性，并将这些特征相关联 与IBM的临床指标。此外，将使用药理学方法来定义机制 调节IBM中T细胞衰老。我们将测试衰老肌肉T细胞促进的中心假设 IBM的严重程度和进展。在初步研究中，我们表明KRLG1+CD8+的频率 IBM患者的血液中衰老样的T细胞升高。虽然KRLG1+ CD8+ T细胞与 疾病持续时间，它们与IBM的严重程度无关。鉴于免疫反应可能大不相同 在血液和受影响的组织之间，具有高分辨率分析免疫反应的机械研究 在IBM中，需要在IBM中确定衰老T细胞和IBM之间的关系。中心假设 这项调查将通过解决两个具体目标来测试。在特定的目标1中，我们将定义分子 衰老肌肉T细胞的特征及其与疾病的严重程度和进展的关系。缺乏工具 肌肉中严格表型T细胞群体使研究这些细胞很难确定它们 IBM的功能。因此，将使用创新的高维质量成像平台来解决这个问题 限制，并确定衰老T细胞和IBM之间的关系。在特定的目标2中，我们将 确定鼻溶疗法对消融衰老CD8+ T细胞的能力，这将提供机械洞察力 关于IBM期间T细胞衰老的调节。拟议的研究很重要，因为它将建立 定义IBM中T细胞反应失调功能的功能的基础。此外，它将提供初步 支持该疾病的新型治疗方法测试的证据。拟议的研究是 也是创新的，因为它使用质量成像中的最先进的进步来严格询问衰老 IBM中T细胞的表型。鼻溶剂的使用也标志着靶向的创新方法 功能失调的T细胞并定义衰老T细胞在IBM中的作用。拟议的工作总体上承诺 促进我们对免疫系统在IBM发病机理中的作用的理解，并且可能具有 通过指导制定新颖的治疗IBM策略来开发广泛的影响。