Genomic Analysis of Tissue and Cellular Heterogeneity in IPF

项目摘要 特发性肺纤维化（IPF）是一种慢性进行性肺病， mortality.在该资助的前一阶段，我们对microCT进行了批量RNA-seq和microRNA分析， 定义了不同受影响的肺部区域。这项工作导致了许多分子靶点的鉴定， 洞察力，计算方法的发展，以及纤维化转录模型的发展 进展使用强大的高分辨率单细胞分析技术，我们生成了所有细胞的“地图”。 人类细胞在IPF患者中，发现了新的异位和异常细胞群， 远端肺泡细胞内容物与通常填充气道的细胞。这些令人兴奋的发现是 这一更新应用程序的基础，重点是识别驱动变化的信号， 它们的序列和空间组织。本申请的基本假设是， IPF独特的组织病理学特征反映了IPF患者体内稳态细胞网络的破坏， 肺泡龛，激活异常但协调的修复过程，导致向近端化 远端肺的一部分为了解决这一假设，我们组建了一个多学科的专家团队， 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，将执行以下具体目标： 具体目的1：确定在细胞周期中细胞组成和表型变化的具体顺序。 人IPF肺中纤维化的进展。 具体目标2：确定细胞间空间关系、相互作用和连接的变化 在纤维化的不同阶段和纤维化的进展的纤维化生态位的成员。 具体目标3：生成人肺纤维化的系统生物学模型，特别关注 疾病出现和进展的调节剂。 在这个项目完成后，我们将有一个细胞水平，全面的转录调控， 根据疾病独特的组织学特征，建立IPF的机制相关模型。该模型 发现的关键监管模块和随之而来的数据共享和传播工具将是有用的 了解疾病机制和产生新的，有效的和精确的治疗干预。

PROJECT SUMMARY 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.