Defining and Controlling Airway Disease

定义和控制气道疾病

• 批准号: 10579266
• 负责人: Michael J Holtzman
• 金额: $ 94.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579266
• 关键词: 3-Dimensional; Address; Airway Disease; Asthma; Attenuated; Back; Cause of Death; Cell Differentiation process; Cell Proliferation; Cell Reprogramming; Cell Separation; Cell physiology; Cells; Cellular biology; Charge; Chromatin; Chronic Obstructive Pulmonary Disease; Data; Disease; Drug Design; Environment; Epithelial Cells; Extramural Activities; Functional disorder; Genomics; Goals; Homeostasis; Human; Immune; Immune response; Individual; Infection; Interruption; Link; Lung; Medical Research; Mentors; Mission; Mitotic; Molecular; Molecular Target; Morbidity - disease rate; Mucous body substance; National Heart, Lung, and Blood Institute; Pathogenesis; Pathway interactions; Phosphotransferases; Population; Prevention therapy; Production; Proteomics; Public Health; Research; Research Personnel; Resources; Role; Scientist; Structure; Technology; Therapeutic Intervention; Tissues; Training; Transplantation; Universities; Validation; Viral; Work; airway epithelium; airway repair; career development; cell behavior; cellular targeting; chronic respiratory disease; effective therapy; epithelial stem cell; innovation; lung development; mortality; mouse model; multidisciplinary; novel strategies; porcine model; programs; respiratory virus; response to injury; stem cells; translational impact; water channel

Abstract Airway epithelial cells were originally regarded as an inert barrier to the environment, but are now viewed as key regulators of the response to injury and infection with a critical role in airway repair that mimics lung development. Furthermore, altered behavior of this cell population is central to the pathogenesis of common airway diseases such as asthma and COPD, making it essential to understand the mechanisms responsible to normal and abnormal programming of this cell population. My research program is thematically focused on airway epithelial cell programming with the goal of characterizing the molecular basis of airway epithelial cell function and dysfunction for airway homeostasis versus disease. Our work to date has contributed to new paradigms in airway epithelial cell biology, including the first evidence of an active role for airway epithelial cells in directing the immune response towards airway disease and now the first data for an elusive airway progenitor epithelial cell (APEC) population that can be respiratory-virus activated to orchestrate disease and thereby explain how a transient infection could lead to long-term disease. Building on this work, we will focus going forward on creating a new concept for tissue homeostasis versus disease based on a set of transformative paradigms where progenitor cell reprogramming switches a normal airway epithelial barrier to one dominated by mucus production and the consequent morbidity and mortality of airway disease. We will provide the first definition of the key population of airway progenitor epithelial cells and the first mechanisms for how these cells are switched to disease-producing cells, incorporating unprecedented roles for: (1) endogenous viral, water channel, and nucleokine control of mitotic chromatin in these cells; and (2) an exogenous danger loop from these cells to immune cells and back to drive a distinct progenitor-cell kinase now targeted with structure-based drug design to interrupt mucus production. Translational impact also derives from new mouse and pig models and validation in humans with comparable disease. This substrate is combined with new approaches to cell isolation, 3D manipulation, and transplantation based on targets identified from genomic and proteomic analyses. Each of the individual approaches within the overall Program is charged to investigators in training to integrate scientific career development into the mission for medical research and discovery. In addition, the Program relies on vital and sophisticated input from senior pulmonary scientists for additional mentoring and cutting-edge approaches and innovations. The Program also incorporates the wider University and extramural resources to deploy multidisciplinary technologies with outstanding collaborators. Together, we expect our Program to provide a transformative paradigm for true progenitor epithelial cell programming and its role in cell proliferation and differentiation, including skewing towards mucous cell formation and excess mucus production that is central to airway disease. We also fully expect that our studies will identify the first tractable cellular and molecular targets and corresponding therapeutic intervention to attenuate airway disease, consistent with the mission of NHLBI.

抽象的 气道上皮细胞最初被视为环境的惰性障碍，但现在被视为关键 对损伤和感染的反应的调节因子在气道修复中具有关键作用，模仿肺发育。 此外，该细胞种群的行为改变对于普通气道疾病的发病机理至关重要 例如哮喘和COPD，因此必须了解负责正常的机制和 该细胞种群的异常编程。我的研究计划主题专注于气道上皮 细胞编程的目的是表征气道上皮细胞功能的分子基础和 气道稳态与疾病的功能障碍。迄今为止，我们的工作促成了气道的新范例 上皮细胞生物学，包括首先证明气道上皮细胞在指导 对气道疾病的免疫反应，现在是难以捉摸的气道祖细胞的第一个数据 （APEC）可以激活呼吸病毒的人群来编排疾病，从而解释了如何 短暂感染可能导致长期疾病。在这项工作的基础上，我们将集中精力创建 基于一组变革性范式的组织稳态与疾病的新概念 祖细胞重编程将正常气道上皮屏障转换为粘液产生的一个屏障 以及导致气道疾病的发病率和死亡率。我们将提供密钥的第一个定义 气道祖细胞的种群和这些细胞如何切换到的第一个机制 产生疾病的细胞，结合了前所未有的作用：（1）内源性病毒，水通道和 这些细胞中有丝分裂染色质的核定控制； （2）从这些细胞到的外源危险循环 免疫细胞并返回到现在以基于结构的药物设计为目标的独特的祖细胞激酶 中断粘液产生。翻译影响还来自新的鼠标和猪模型以及验证 在患有类似疾病的人类中。该基材与新的细胞隔离方法结合了3D 根据基因组和蛋白质组学分析确定的靶标进行操作和移植。每个 总体计划中的个别方法向调查人员收取培训，以整合科学 职业发展成为医学研究和发现的使命。此外，该计划依靠至关重要 以及高级肺科学家的精致意见，以提供其他指导和尖端方法 和创新。该计划还包含更广泛的大学和外部资源来部署 具有出色合作者的多学科技术。一起，我们希望我们的计划提供 真正的祖细胞上皮细胞编程及其在细胞增殖和 分化，包括偏向粘液细胞形成和过量的粘液产生，这是 气道疾病。我们还完全期望我们的研究将确定第一个可牵引的细胞和分子靶标 与NHLBI的任务一致的相应的治疗干预措施减弱了气道疾病。