Airway epithelial cell gene regulation: new mechanisms and therapeutic strategies

气道上皮细胞基因调控：新机制和治疗策略

• 批准号: 10586412
• 负责人: David J Erle
• 金额: $ 9.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2022-11-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10586412
• 关键词: Address; Airway Disease; Asthma; Biological Assay; Biology; Cell Culture Techniques; Cell Line; Cell physiology; Cells; ChIP-seq; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Disease; Environment; Epithelial; Epithelial Cells; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Human; Lung diseases; Mediating; Molecular; Nucleic Acid Regulatory Sequences; Pathogenicity; Play; Population; Positioning Attribute; Regulator Genes; Reporter; Research Personnel; Resources; Role; System; Technology; Therapeutic; Transgenic Mice; Work; airway epithelium; airway obstruction; career; cell type; cytokine; design; disorder risk; experimental study; genetic variant; insight; lung health; mouse model; novel strategies; prevent; response; single-cell RNA sequencing

PROJECT SUMMARY The epithelium that lines the airway comprises a variety of specialized cell types that play essential roles in lung health. Changes in the epithelium are prominent features of asthma and other common lung diseases. During normal differentiation, dramatic changes in gene expression are required for the development of the unique functional capabilities of the basal, secretory, and ciliated cell populations within the epithelium. Furthermore, in airway disease, each cell type has distinctive gene expression changes in response to pathogenic cytokines. Over the past two decades, we have used transgenic mouse modeling, human cell culture, and clinical studies to identify molecular mechanisms that underlie changes in epithelial gene expression that contribute to airway obstruction in asthma. Although we and others have gained tremendous insights from mouse models, our overall goal of understanding the biology underlying asthma and other human airway diseases has increasingly led us to focus on developing appropriate human experimental systems. In the past several years, we and our collaborators have developed a set of powerful approaches including single cell RNA-seq, ChIP-seq, massively parallel reporter assays, and CRISPR-mediated gene editing, to address mechanistic questions in primary human airway epithelial cells. These approaches now enable us to perform potentially groundbreaking experiments that give new insights into airway epithelial cell complexity, identify key regulators of gene expression and epithelial cell function, and reveal how specific airway epithelial gene regulators contribute to asthma and other airway diseases. Most disease-associated genetic variants are found in regulatory regions, and our work has important implications for understanding genetic contributions to airway disease risk. We will also work to apply insights about gene regulation to develop approaches for therapeutic reprogramming of the epithelium to prevent, cure, or treat disease. The environment at UCSF provides access to creative collaborators, cutting-edge technologies, and key clinical resources and affords outstanding opportunities for working with early career investigators who will be well positioned to continue to move the field forward.

项目概要 气道上皮由多种特殊细胞类型组成，在肺中发挥重要作用 健康。上皮细胞的变化是哮喘和其他常见肺部疾病的显着特征。期间 正常分化，基因表达的巨大变化是独特的发育所必需的 上皮内基底细胞、分泌细胞和纤毛细胞群的功能。此外，在 气道疾病中，每种细胞类型都有独特的基因表达变化来响应致病细胞因子。 在过去的二十年里，我们使用了转基因小鼠模型、人类细胞培养和临床研究 确定导致气道上皮基因表达变化的分子机制 哮喘阻塞。尽管我们和其他人从小鼠模型中获得了巨大的见解，但我们的整体 了解哮喘和其他人类呼吸道疾病的生物学基础的目标日益引导我们 专注于开发适当的人体实验系统。在过去的几年里，我们和我们的 合作者开发了一系列强大的方法，包括单细胞 RNA-seq、ChIP-seq、大规模 平行报告分析和 CRISPR 介导的基因编辑，以解决初级中的机制问题 人气道上皮细胞。这些方法现在使我们能够执行潜在的突破性任务 实验为气道上皮细胞的复杂性提供了新的见解，确定了基因的关键调节因子 表达和上皮细胞功能，并揭示特定气道上皮基因调节因子如何促进 哮喘和其他呼吸道疾病。大多数与疾病相关的遗传变异都存在于调控区域， 我们的工作对于了解遗传对气道疾病风险的影响具有重要意义。我们将 还致力于应用有关基因调控的见解来开发治疗性重编程方法 上皮细胞以预防、治愈或治疗疾病。加州大学旧金山分校的环境提供了接触创意合作者的机会， 尖端技术和关键临床资源，并为早期合作提供了绝佳的机会 职业调查员将处于有利地位，继续推动该领域向前发展。