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

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测序在肺部疾病中的应用 描述：间质性肺疾病（ILD）是一组异质性的肺部疾病，导致疤痕 仅在美国就有30万人受到影响。这些疾病 可被分类为具有“内在”、“外在”或“自身免疫”病因。一种特殊的慢性 纤维化ILD-特发性肺纤维化（内源性）、慢性过敏性肺炎（外源性），以及 结缔组织相关ILD（自身免疫性）-可表现为常见的间质性肺炎（UIP）模式 有相似的症状和肺功能测试。然而，他们的努力和 治疗是不同的。其中，特发性肺纤维化的死亡率最高， 患者，并给予诊断后三至五年的中位生存时间。此外，不正确的诊断 对特发性肺纤维化患者进行免疫抑制治疗可以 严重加重了他们的病情。因此，在最低限度内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 对病人几乎没有风险，并提供了一个窗口，了解他们的健康状况; Naftali Kaminski和他的研究小组证明，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- scRNA-seq技术，我们希望阐明ILD的疾病特异性免疫机制 在外周血中捕获UIP模式（UIP ILD）。具体而言，目标1将决定 疾病特异性免疫畸变可以通过外周血细胞类型组成和基因捕获 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ILD。目的2将确定是否有不同的抗原，驱动疾病， UIP ILD患者，并将通过B和T细胞来表征这些疾病中的适应性免疫状况 受体分析本研究的目标有三个方面：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，该模型将诊断给定基因的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 将有望为临床诊断和治疗类似表现的UIP ILD患者提供信息。的 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， 物理学家兼科学家

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.