Defining and Controlling Airway Disease

定义和控制气道疾病

• 批准号: 9889988
• 负责人: Michael J Holtzman
• 金额: $ 94.4万
• 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/9889988
• 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; Chronic Obstructive Airway Disease; Data; Disease; Drug Design; Environment; Epithelial Cells; Extramural Activities; Family suidae; Functional disorder; Genomics; Goals; Homeostasis; Human; Immune; Immune response; Individual; Infection; Interruption; Lead; Link; Lung; Lung diseases; Medical Research; Mentors; Mission; Mitotic; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mucous body substance; Mus; 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; base; career development; cell behavior; cellular targeting; effective therapy; epithelial stem cell; innovation; lung development; mortality; multidisciplinary; novel strategies; programs; repaired; 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.

摘要 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。 调节对损伤和感染的反应，在模拟肺发育的气道修复中起关键作用。 此外，这种细胞群的行为改变是常见气道疾病发病机制的核心 如哮喘和COPD，这使得了解正常和 这些细胞群体的异常编程。我的研究项目主要集中在气道上皮 细胞编程，目的是表征气道上皮细胞功能的分子基础， 气道内稳态功能障碍与疾病。我们迄今为止的工作为气道的新范式做出了贡献 上皮细胞生物学，包括气道上皮细胞在引导呼吸道上皮细胞分化中的积极作用的第一个证据。 对气道疾病的免疫反应，现在是第一个数据，一个难以捉摸的气道祖上皮细胞 （亚太经合组织）的人口，可以被病毒激活，以协调疾病，从而解释如何 短暂的感染可能导致长期的疾病。在这项工作的基础上，我们将集中精力创造 基于一组变革性范例的组织稳态与疾病的新概念， 祖细胞重编程将正常的气道上皮屏障转变为由粘液产生主导的屏障 以及随之而来的气道疾病的发病率和死亡率。我们将提供键的第一个定义 气道祖上皮细胞的群体和这些细胞如何被转换为 致病细胞，包括前所未有的作用：（1）内源性病毒，水通道， 核因子控制这些细胞中的有丝分裂染色质;和（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 以阻止粘液的产生。翻译的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。这种基质与细胞分离的新方法相结合， 基于基因组和蛋白质组分析确定的靶点进行操纵和移植。每个 在整个计划中，研究人员负责培训研究人员，以整合科学方法， 职业发展成为医学研究和发现的使命。此外，该计划还依赖于重要的 以及高级肺部科学家的复杂投入，以获得额外的指导和尖端方法 和创新。该计划还结合了更广泛的大学和校外资源部署 多学科技术与杰出的合作者。总之，我们希望我们的计划提供一个 真祖上皮细胞编程的变革范例及其在细胞增殖和 分化，包括倾向于粘液细胞形成和过度粘液产生，这是核心 呼吸道疾病我们也完全期待我们的研究将确定第一个易处理的细胞和分子靶点 以及相应的治疗干预以减轻气道疾病，这与NHLBI的使命一致。