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

项目摘要/摘要：确定慢性纤维化间质中疾病特异性免疫细胞的转移 肺疾病的单细胞RNA测序 描述：间质性肺疾病(ILDS)是一组引起瘢痕形成的不同种类的肺部疾病。 仅在美国，估计就有30万人受到影响。这些疾病 可分为“内源性”、“外源性”或“自身免疫性”病因。慢性病的一个特殊子集 纤维性ILDS-特发性肺纤维化(内源性)，慢性过敏性肺炎(外源性)，以及 结缔组织相关性ILD(自身免疫)-可表现为常见的间质性肺炎(UIP)类型 有相似的症状和肺功能测试。然而，他们的预测和 治疗方法是不同的。其中，特发性肺纤维化与#年最高的死亡率有关 确诊后，患者的平均存活时间为三到五年。此外，错误的诊断 对特发性肺纤维化患者进行免疫抑制治疗可以 大大加重了他们的病情。因此，在最低限度上准确诊断这些患者是至关重要的。 侵入性方式，如通过外周采血。获取外周血单核细胞姿势 对患者几乎没有风险，并提供了了解他们健康的窗口；该应用程序的发起人Dr。 Naftali Kaminski和他的团队证明了PBMC的细胞类型组成和基因表达 征象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ILDS的疾病特异性免疫机制。 在外周血中捕捉到uIP模式(UIP ILDs)。特别是，目标1将决定是否 外周血细胞类型组成和基因可捕获疾病特异性免疫异常 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，并将通过B和T细胞表征这些疾病的适应性免疫格局 受体分析。这项研究的目标有三个：1)表征特定疾病的外周血液 生物标志物，2)创建临床决策模型，该模型将诊断给定的UIP ILD亚型基因 表达，细胞组成，T和B细胞受体谱系，以及患者的临床信息，以及3)获得 深入了解UIP ILD的发病机制，促进患者治疗。综上所述，拟议的研究 有望为临床诊断和治疗类似UIP ILDS的患者提供参考。这个 奖学金还包括一项培训计划，该计划具有宝贵的学习经验，有助于申请者发展为 医生兼科学家。

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.