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: 9915971
• 负责人: David J Erle
• 金额: $ 96.69万
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9915971
• 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; Epithelium; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Health; Human; Lung; 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; 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.

项目摘要 线条线的上皮包括各种在肺中起重要作用的专业细胞类型 健康。上皮的变化是哮喘和其他常见肺部疾病的突出特征。期间 正常分化，基因表达的急剧变化是独特的发展 上皮内基底，分泌和纤毛细胞群的功能能力。此外，在 气道疾病，每种细胞类型都在响应致病细胞因子的响应中具有独特的基因表达变化。 在过去的二十年中，我们使用了转基因小鼠建模，人类细胞培养和临床研究 确定基于上皮基因表达变化的分子机制，这有助于气道 哮喘的阻塞。尽管我们和其他人从鼠标模型中获得了巨大的见解，但我们的总体 了解哮喘和其他人类气道疾病的生物学的目标越来越多地导致我们 专注于开发适当的人类实验系统。在过去的几年中，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 并行记者测定和CRISPR介导的基因编辑，以解决主要的机械问题 人气道上皮细胞。这些方法现在使我们能够执行潜在的开创性 为气道上皮细胞复杂性提供新见解的实验，识别基因的关键调节剂 表达和上皮细胞功能，并揭示特定气道上皮基因调节剂如何有助于 哮喘和其他气道疾病。大多数与疾病相关的遗传变异都在调节区域发现， 我们的工作对理解对气道疾病风险的遗传贡献具有重要意义。我们将 还可以利用有关基因调节的见解，以开发用于治疗重新编程的方法 预防，治愈或治疗疾病的上皮。 UCSF的环境提供了对创意合作者的访问， 尖端技术和关键的临床资源，为与早期合作提供了出色的机会 职业调查人员将有能力继续前进。