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: 10579268
• 负责人: David J Erle
• 金额: $ 96.9万
• 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/10579268
• 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; Creativeness; Development; Disease; Environment; Epithelial Cells; Epithelium; 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.

项目总结