Genomic Analysis of Tissue and Cellular Heterogeneity in IPF

IPF 组织和细胞异质性的基因组分析

• 批准号: 10540017
• 负责人: PANAGIOTIS V BENOS
• 金额: $ 75.02万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-14 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540017
• 关键词: Address; Affect; Alveolar; Animal Model; Architecture; Bioinformatics; Biomedical Engineering; Blood Vessels; Cell Nucleus; Cells; Cellular biology; Chronic; Collagen; Computational Biology; Computing Methodologies; Connective Tissue Diseases; Data; Deposition; Development; Disease; Distal; Epithelial Cells; Extracellular Matrix; FDA approved; Fibrosis; Foundations; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genomics; Grant; Heterogeneity; Histologic; Histology; Human; Image; Immune; Immunity; Intervention; Lead; Lung; Lung diseases; Machine Learning; Maps; Metadata; Methods; Modeling; Molecular; Molecular Biology; Molecular Target; Morbidity - disease rate; Multiomic Data; Myofibroblast; Pathology; Patients; Persons; Pharmaceutical Preparations; Phenotype; Population; Population Replacements; Process; Proteomics; Pulmonary Fibrosis; Pulmonary Inflammation; Resolution; Sampling; Severity of illness; Signal Transduction; Systems Biology; Techniques; Technology; Therapeutic Intervention; Tissues; Usual Interstitial Pneumonia; Validation; Work; allograft rejection; base; causal model; cell injury; computer science; data dissemination; data sharing; design; effective intervention; experimental study; fibrotic interstitial lung disease; human model; idiopathic pulmonary fibrosis; insight; lung allograft; member; method development; miRNA expression profiling; microCT; mortality; multidisciplinary; novel; pre-clinical; predictive modeling; repaired; single cell technology; statistics; tissue resource; tool; transcriptome; transcriptome sequencing

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.

项目概要 特发性肺纤维化（IPF）是一种慢性进行性肺部疾病，发病率很高， 在本次资助的前一阶段，我们对 microCT 进行了批量 RNA 测序和 microRNA 分析。 这项工作确定了受不同影响的肺部区域，并确定了许多分子靶点和 见解、计算方法的发展以及纤维化转录模型的发展 利用强大的单细胞分析高分辨率技术，我们生成了所有细胞的“地图” 研究人员对 IPF 患者的人类细胞进行了研究，发现了新的、异位的和异常的细胞群，并替换了 这些令人兴奋的发现是通常存在于气道中的细胞的远端肺泡细胞含量。 这个更新应用程序的基础，重点是识别驱动我们改变的信号 确定了它们的顺序和空间组织，该应用的假设是： IPF 独特的组织病理学特征反映了体内稳态细胞网络的破坏 肺泡生态位，激活异常但协调的修复过程，导致近端化 为了解决这一假设，我们组建了一个多学科的肺部专家团队。 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实现以下具体目标： 具体目标 1：确定细胞组成和表型变化的具体顺序 人 IPF 肺纤维化的进展。 具体目标 2：识别细胞之间空间关系、相互作用和连接的变化 处于纤维化和纤维化进展不同阶段的纤维化生态位的成员。 具体目标 3：生成人类肺纤维化的系统生物学模型，特别关注 疾病发生和进展的调节因子。 这个项目完成后，我们将有一个细胞水平的、全面的转录调控， 基于该疾病独特的组织学特征的 IPF 机制相关模型。 发现关键监管模块和随附的数据共享和传播工具将很有用 了解疾病机制并产生新颖、有效和精确的治疗干预措施。