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.

摘要 呼吸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 对损伤和感染的反应的调节，在模仿肺发育的呼吸道修复中发挥关键作用。 此外，这种细胞群的行为改变是常见呼吸道疾病发病机制的核心。 如哮喘和慢性阻塞性肺病，因此有必要了解导致正常和 这个细胞群体的异常编程。我的研究项目以呼吸道上皮为主题 细胞编程，目的是表征呼吸道上皮细胞功能的分子基础和 呼吸道动态平衡功能障碍与疾病。到目前为止，我们的工作为呼吸道领域的新范式做出了贡献。 上皮细胞生物学，包括第一个证据表明呼吸道上皮细胞在引导 对呼吸道疾病的免疫反应，现在是难以捉摸的呼吸道前体上皮细胞的第一个数据 (亚太经合组织)人群可以被呼吸道病毒激活以协调疾病，从而解释 短暂的感染可能会导致长期的疾病。在这项工作的基础上，我们将专注于创造 基于一系列变革性范式的组织动态平衡对抗疾病的新概念，其中 前体细胞重编程将正常的呼吸道上皮屏障转换为以粘液产生为主的屏障 以及随之而来的呼吸道疾病的发病率和死亡率。我们将提供密钥的第一个定义 气道祖细胞的数量及其转化机制的初步研究 致病细胞，在以下方面发挥前所未有的作用：(1)内源性病毒、水通道和 核因子对这些细胞有丝分裂染色质的控制；以及(2)从这些细胞到 免疫细胞和回来驱动一种独特的前体细胞激酶，现在以基于结构的药物设计为靶点 来干扰粘液的产生。翻译的影响也来自新的老鼠和猪的模型和验证 在患有类似疾病的人类身上。这种底物与细胞分离的新方法相结合，3D 根据基因组和蛋白质组分析确定的目标进行操作和移植。每一位 整个计划中的个别方法在培训中向调查人员收取费用，以整合科学 把事业发展转变为医学研究和发现的使命。此外，该计划依赖于至关重要的 以及来自资深肺科科学家的复杂投入，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来部署 多学科技术与杰出的合作者。我们期待着我们的计划能够提供一个 真正的祖细胞上皮细胞编程的变革性范式及其在细胞增殖和 分化，包括偏向粘液细胞形成和过度粘液产生，这是 呼吸道疾病。我们也完全期待我们的研究将确定第一个容易处理的细胞和分子目标。 以及相应的治疗干预，以减轻呼吸道疾病，与NHLBI的使命一致。