Genomic Analysis of Tissue and Cellular Heterogeneity in IPF

R01的项目总结和补充 特发性肺纤维化(IPF)是一种慢性进展性肺部疾病，具有显著的发病率和 死亡率。在这笔赠款的前一阶段，我们进行了microCT的批量RNA-seq和microRNA分析 定义了不同的受影响的肺区。这项工作导致了许多分子目标的识别和 洞察，计算方法的发展，以及纤维化转录模型的发展 进步。使用强大的高分辨率单细胞图谱技术，我们生成了一张所有 人细胞在特发性肺纤维化患者中发现了新的、异位和异常的细胞群，并取代了 远端肺泡的细胞内容物，通常位于呼吸道内。这些令人兴奋的发现是 此续订应用程序的基础侧重于识别推动我们的变化的信号 识别、它们的序列和它们的空间组织。这个应用程序背后的假设是 特发性肺间质纤维化独特的组织病理学特征反映了内环境平衡细胞网络的破坏。 肺泡龛，激活一个异常但协调的修复过程，导致近似化 在远端肺中。为了解决这一假设，我们组建了一个多学科的肺病专家团队。 纤维化、基因组学、蛋白质组学、计算生物学、计算机科学、细胞和分子生物学、统计学、 成像、生物工程、病理学和生物信息学，将执行以下特定目标： 具体目标1：确定细胞组成和表型变化的特定序列 人肺间质纤维化的进展。 具体目标2：确定细胞之间的空间关系、相互作用和连接的变化 纤维化生态位中处于不同纤维化阶段和纤维化进展的成员。 具体目标3：建立人肺纤维化的系统生物学模型 疾病发生和发展的调节者。 在这个项目完成后，我们将拥有一个细胞水平，全面的转录调控， 基于该病独特的组织学特征的IPF的力学相关模型。模型，模型， 已发现的关键监管模块以及随附的数据共享和传播工具将是有用的 用于了解疾病机制和产生新的、有效和精确的治疗干预措施。

PROJECT SUMMARY AND SUPPLEMENT TO R01 Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive lung disease with significant morbidity and mortality. In the previous period of this grant, we performed bulk RNA-seq and microRNA profiling of microCT defined differentially affected lung regions. This work led to identification of numerous molecular targets and insights, development of computational methods, and development of a transcriptional model of fibrosis progression. Using the powerful high-resolution technologies of single cell profiling, we generated a ‘map’ of all human cells in patients with IPF, discovered novel, ectopic and aberrant cell populations, and replacement of the distal alveolar cellular content with cells that usually populate the airways. These exciting findings are foundations of this renewal application that focuses on identification of the signals that drive the changes we identified, their sequence and their spatial organization. The hypothesis underlying this application is that the unique histopathologic features of IPF reflect a disruption in the homeostatic cellular networks in alveolar niche, that activates an aberrant but coordinated repair process that leads to the proximalization of the distal lung. To address this hypothesis, we have assembled a multi-disciplinary team of experts in lung fibrosis, genomics, proteomics, computational biology, computer science, cell and molecular biology, statistics, imaging, bioengineering, pathology, and bioinformatics that will perform the following specific aims: Specific Aim 1: To identify the specific sequence of changes in cell compositions and phenotypes during the progression of fibrosis in the human IPF lung. Specific Aim 2: To identify the changes in spatial relations, interactions, and connections between cellular members of the fibrotic niche at different stages of fibrosis and progression of fibrosis. Specific Aim 3: Generation of a systems biology model of human pulmonary fibrosis with a specific focus on regulators of disease emergence and progression. At the completion of this project, we will have a cell level, comprehensive transcriptional regulatory, mechanistically relevant model of IPF based on the unique histological features of the disease. The model, the discovered key regulatory modules and the accompanying data sharing, and dissemination tools will be useful for understanding disease mechanisms and generation of novel, effective and precise therapeutic interventions.