Identifying Disease-Specific Immune Cell Shifts in Chronic Fibrotic Interstitial Lung Diseases with Single-Cell RNA Sequencing

通过单细胞 RNA 测序鉴定慢性纤维化间质性肺疾病中疾病特异性免疫细胞的变化

• 批准号: 10388606
• 负责人: Amy Yue-Ting Zhao
• 金额: $ 5.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-16 至 2026-02-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388606
• 关键词: Affect; Antigen Receptors; Antigens; Autoimmune; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Biological Assay; Biological Markers; Biopsy; Blood; Blood Cells; Blood specimen; Cells; Chronic; Clinical; Clinical Treatment; Connective Tissue; Connective Tissue Diseases; Data; Data Science; Decision Modeling; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Etiology; Extrinsic allergic alveolitis; Fellowship; Fibrosis; Foundations; Gene Expression; Gene Expression Profile; Goals; Gold; Guidelines; Health; Hypersensitivity; Image; Immune; Immune response; Immunophenotyping; Immunosuppressive Agents; Interstitial Lung Diseases; Learning; Lung; Lung diseases; Methods; Modality; Multiomic Data; Newly Diagnosed; Patients; Pattern; Peripheral Blood Mononuclear Cell; Persons; Physicians; Physiological; Precipitins; Process; Prognosis; Pulmonary Pathology; Pulmonary function tests; Research; Risk; Sampling; Scientist; Scleroderma; Serum; Severity of illness; Structure of parenchyma of lung; Symptoms; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Training; United States; Usual Interstitial Pneumonia; Work; accurate diagnosis; antigen detection; career; cell type; clinical diagnostics; cohort; complementarity-determining region 3; disease diagnosis; disorder subtype; experience; fibrotic interstitial lung disease; fibrotic lung; idiopathic pulmonary fibrosis; insight; minimally invasive; mortality; novel; peripheral blood; prevent; radiological imaging; receptor; single-cell RNA sequencing

Project Summary/Abstract: Identifying Disease-Specific Immune Cell Shifts in Chronic Fibrotic Interstitial Lung Diseases with Single-Cell RNA Sequencing Description: Interstitial lung diseases (ILDs) are a heterogeneous group of lung disorders that cause scarring of the lung parenchyma and affect an estimated 300,000 people in the United States alone. These diseases can be categorized as having “intrinsic,” “extrinsic,” or “auto-immune” etiologies. A particular subset of chronic fibrotic ILDs – idiopathic pulmonary fibrosis (intrinsic), chronic hypersensitivity pneumonitis (extrinsic), and connective tissue-associated ILD (auto-immune) – can present with usual interstitial pneumonia (UIP) patterns on imaging and have similar symptoms and pulmonary function tests. However, their prognoses and treatments are distinct. Among them, idiopathic pulmonary fibrosis is associated with the highest mortality in patients and confers a median survival time after diagnosis of three to five years. Moreover, incorrect diagnosis and administration of immunosuppressive treatments to patients with idiopathic pulmonary fibrosis can significantly worsen their disease. Therefore, it is critical to accurately diagnose these patients in a minimally invasive manner, such as through peripheral blood draws. Obtaining peripheral blood mononuclear cells poses little risk to patients and provides a window into their health; previous work by the application’s sponsor, Dr. Naftali Kaminski, and his group demonstrated that PBMC cell-type composition and gene expression signatures can distinguish idiopathic pulmonary fibrosis disease severity. Leveraging single-cell RNA- sequencing (scRNA-seq) technology, we hope to elucidate the disease-specific immune mechanisms of ILDs with UIP patterns (UIP ILDs) captured in the peripheral blood. In particular, Aim 1 will determine whether disease-specific immune aberrations can be captured by peripheral blood cell-type composition and gene expression signatures in idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, and connective tissue disease-associated ILD. Aim 2 will ascertain whether there are distinct antigens that drive disease in UIP ILD patients and will characterize the adaptive immune landscape in these diseases through B and T cell receptor profiling. The goals of this study are three-fold: 1) to characterize disease-specific peripheral blood biomarkers, 2) to create a clinical decision model that would diagnose a UIP ILD subtype given gene expression, cell composition, T and B cell receptor repertoires, and patient clinical information, and 3) to gain insight into UIP ILD disease mechanisms to advance patient therapeutics. In summary, the proposed research will hopefully inform clinical diagnostics and treatments for patients with similarly presenting UIP ILDs. The fellowship also includes a training plan with valuable learning experiences for the applicant’s development as a physician-scientist.

项目摘要/摘要：识别慢性纤维化间质中疾病特异性免疫细胞的变化 单细胞 RNA 测序研究肺部疾病 描述：间质性肺疾病 (ILD) 是一组异质性肺部疾病，可导致疤痕 据估计，仅在美国就有 300,000 人受到影响。这些疾病 可分为“内在”、“外在”或“自身免疫”病因。慢性病的一个特定子集 纤维化 ILD – 特发性肺纤维化（内在）、慢性过敏性肺炎（外在）和 结缔组织相关 ILD（自身免疫）——可表现为常见的间质性肺炎 (UIP) 模式 在影像学和肺功能检查上有相似的症状。然而，他们的预测和 治疗方法各有不同。其中，特发性肺纤维化与死亡率最高 患者并给予诊断后三到五年的中位生存时间。此外，诊断错误 对特发性肺纤维化患者进行免疫抑制治疗可以 使他们的疾病明显恶化。因此，以最少的时间准确诊断这些患者至关重要 侵入性方式，例如通过外周血抽取。外周血单个核细胞的获取 对患者的风险很小，并为了解他们的健康提供了一个窗口；该应用程序的发起人博士之前的工作 Naftali Kaminski 和他的团队证明了 PBMC 细胞类型组成和基因表达 特征可以区分特发性肺纤维化疾病的严重程度。利用单细胞 RNA 测序（scRNA-seq）技术，我们希望阐明ILD的疾病特异性免疫机制 外周血中捕获的 UIP 模式（UIP ILD）。特别是，目标 1 将确定是否 疾病特异性免疫异常可以通过外周血细胞类型组成和基因来捕获 特发性肺纤维化、慢性过敏性肺炎和结缔组织中的表达特征 组织疾病相关的 ILD。目标 2 将确定是否存在导致疾病的不同抗原 UIP ILD 患者，将通过 B 和 T 细胞表征这些疾病中的适应性免疫景观 受体分析。本研究的目标有三个：1）表征疾病特异性外周血 生物标志物，2) 创建临床决策模型，根据给定基因诊断 UIP ILD 亚型 表达、细胞组成、T 和 B 细胞受体库以及患者临床信息，以及 3) 获得 深入了解 UIP ILD 疾病机制以推进患者治疗。总之，拟议的研究 希望能为患有类似 UIP ILD 的患者提供临床诊断和治疗信息。这 奖学金还包括一个培训计划，为申请人的发展提供宝贵的学习经验 医生科学家。