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.

项目摘要 特发性肺纤维化（IPF）是一种慢性进行性肺部疾病，发病率明显 死亡。在这笔赠款的前期，我们进行了Microct的大量RNA-Seq和MicroRNA分析 定义的受影响不同的肺部区域。这项工作导致识别众多分子靶标，并且 见解，计算方法的发展以及纤维化转录模型的发展 进展。使用强大的单细胞分析的高分辨率技术，我们生成了所有人的“地图” IPF患者的人类细胞，发现新颖，异位和异常细胞群体，并替代 牙槽远端的细胞含量，通常填充气道的细胞。这些令人兴奋的发现是 该更新应用的基础，重点是识别驱动我们更改的信号 确定，它们的顺序和空间组织。该申请的基础假设是 IPF的独特组织病理学特征反映了稳态细胞网络中的破坏 肺泡的利基市场，激活了一个异常但协调的维修过程，导致近端化 远端肺。为了解决这一假设，我们组建了一个肺部的多学科专家团队 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，病理和生物信息学将执行以下特定目的： 特定目的1：确定细胞组成和表型变化的特定顺序 人IPF肺中纤维化的进展。 特定目的2：确定空间关系，相互作用和蜂窝之间的连接的变化 在纤维化的不同阶段和纤维化进展的不同阶段的纤维化生态位成员。 特定目的3：生成人类肺纤维化的系统生物学模型，以特定的重点 疾病出现和进展的调节因子。 该项目完成时，我们将拥有一个细胞水平，全面的转录调节性， IPF与机械相关的模型基于该疾病的独特组织学特征。模型， 发现的关键监管模块和参与的数据共享以及传播工具将很有用 了解疾病机制和新颖，有效和精确的治疗干预措施的产生。