Defining and Controlling Airway Disease

定义和控制气道疾病

• 批准号: 10352375
• 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/10352375
• 关键词: 3-Dimensional; Address; Airway Disease; Asthma; Attenuated; Back; Cause of Death; Cell Differentiation process; Cell Proliferation; 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; Lead; 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; base; 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认为是环境的惰性屏障，但现在被视为关键 对损伤和感染反应的调节剂，在模拟肺部发育的气道修复中发挥关键作用。 此外，该细胞群行为的改变是常见气道疾病发病机制的核心 例如哮喘和慢性阻塞性肺病，因此了解正常和慢性阻塞性肺病的机制至关重要 该细胞群的异常编程。我的研究项目的主题是气道上皮 细胞编程，旨在表征气道上皮细胞功能的分子基础， 气道稳态功能障碍与疾病。迄今为止，我们的工作为气道领域的新范例做出了贡献 上皮细胞生物学，包括气道上皮细胞在指导气道上皮细胞的积极作用的第一个证据 对气道疾病的免疫反应，现在是难以捉摸的气道祖上皮细胞的第一个数据 （APEC）人群可以被呼吸道病毒激活以协调疾病，从而解释如何 短暂的感染可能导致长期疾病。在这项工作的基础上，我们将继续致力于创造 基于一组变革范式的组织稳态与疾病的新概念，其中 祖细胞重编程将正常气道上皮屏障转变为以粘液产生为主的屏障 以及随之而来的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 气道祖上皮细胞群以及这些细胞如何转换的第一个机制 产生疾病的细胞，具有前所未有的作用：（1）内源性病毒、水通道和 这些细胞中核因子控制有丝分裂染色质； (2) 从这些细胞到 免疫细胞并返回驱动一种独特的祖细胞激酶，现在以基于结构的药物设计为目标 中断粘液的产生。转化影响也来自新的小鼠和猪模型和验证 在患有类似疾病的人类中。该基质与细胞分离、3D 技术等新方法相结合 根据基因组和蛋白质组分析确定的目标进行操作和移植。每个 整个计划中的个别方法由研究人员负责培训以整合科学 职业发展融入医学研究和发现的使命。此外，该计划依赖于重要的 以及高级肺部科学家的复杂投入，以提供额外的指导和尖端方法 和创新。该计划还整合了更广泛的大学和校外资源来部署 与杰出合作者的多学科技术。我们共同期望我们的计划能够提供 真正的祖上皮细胞编程的变革范式及其在细胞增殖和细胞增殖中的作用 分化，包括倾向于粘液细胞形成和过量粘液产生，这是细胞分化的核心 气道疾病。我们也完全期望我们的研究将确定第一个易于处理的细胞和分子靶点 以及相应的治疗干预措施以减轻气道疾病，这与 NHLBI 的使命一致。