Airway Goblet Cells: Friend or Foe?

气道杯状细胞：朋友还是敌人？

• 批准号: 8355114
• 负责人: DAVID A STOLTZ
• 金额: $ 226.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8355114
• 关键词: Address; Affect; American; Animal Model; Asthma; Award; Biology; Cells; Chronic Obstructive Airway Disease; Clinical Medicine; Cystic Fibrosis; Disease; Disease Outcome; Disease model; Family suidae; Friends; Genes; Goblet Cells; Health; Health Care Costs; Herpesviridae; Human; Hyperplasia; Lead; Lung; Lung diseases; Maintenance; Metaplasia; Mission; Modeling; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Mus; Pathogenesis; Process; Production; Public Health; Research; Research Proposals; Role; Sterility; Study models; System; Therapeutic; Therapeutic Effect; Translations; abstracting; antimicrobial; disease phenotype; high risk; human disease; improved; innovation; insight; mortality; novel; novel therapeutic intervention; programs; public health relevance; response; therapeutic development; thymidine kinase 1

DESCRIPTION (Provided by the applicant) Abstract: Lung health is critically dependent on the maintenance of near sterile airways, a process involving mucus production, airway antimicrobial factors, and mucociliary clearance. The contribution of the goblet cell, a specialized airway cell, to this first line of lung defense s largely unknown. Furthermore, the most common pulmonary disorders, and those associated with the highest morbidity and mortality, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) have, as key and overlapping features, increased goblet cells and mucus hypersecretion. For these reasons, the current paradigm for disease pathogenesis suggests that inhibiting mucus hypersecretion will have beneficial and therapeutic effects in these diseases - despite lack of strong evidence to support this approach in human studies or disease models. An alternative paradigm is that goblet cells and mucus are beneficial and that targeting mucus hypersecretion will have no therapeutic benefit, and may in fact be a harmful strategy. In this high risk, yet potentially paradigm shifting proposal we address this relatively simple idea. The objective of this proposal is to understand the role of goblet cells an mucus in maintenance of the normal lung and in response to airway insults and during disease. The central hypothesis is that goblet cells and mucus are required for airway defense and that lack of goblet cells and mucus will worsen, not improve, airway disease outcomes. In these studies, we will broadly ask three questions: First, are goblet cells and mucus required for maintaining normal lungs? Second, are goblet cells and mucus important for responding to airway insults? Third, are goblet cell metaplasia/hyperplasia and mucus hypersecretion beneficial in diseased lungs? Most airway studies, to date, have been performed in murine models limiting their applicability to humans due to important differences between the murine and human lung and lack of murine airway disease models that closely mimic human disease phenotypes. Since porcine and human airway/lung biology are very similar we will perform our studies in pigs. We will investigate goblet cell and mucus biology by conditionally targeting airway goblet cells with the herpes virus type 1 thymidine kinase system in wild-type and CF pigs. This research proposal is well-suited to the New Innovator Award program because it challenges a current paradigm, utilizes a porcine animal model that closely mimics human airway biology, and uses the CF pig model which represents the first non-murine animal model in which a gene responsible for a human disease has been disrupted. These studies have significant public health relevance because findings should lead to novel mechanistic insights and therapeutic development thereby having a high potential impact on many human airway diseases including asthma, COPD, and CF which affect nearly 50 million Americans and are associated with over 45 billion dollars in annual healthcare costs. Public Health Relevance: This highly innovative and potentially paradigm shifting research is important for public health because understanding the roles of goblet cells and mucus will have a critical impact on developing new therapeutic interventions for airway diseases such as COPD, CF, and asthma. Furthermore, the proposed research is germane to NIH's mission focusing on discoveries related to disease pathogenesis and translation of these studies to clinical medicine.

描述（由申请人提供） 摘要：肺健康严重依赖于维持接近无菌的气道，这是一个涉及粘液产生、气道抗菌因子和粘膜纤毛清除的过程。杯状细胞是一种特化的气道细胞，它在肺防御的第一道防线中的作用尚不清楚。此外，最常见的肺部疾病以及与最高发病率和死亡率相关的那些疾病，包括哮喘、慢性阻塞性肺病（COPD）和囊性纤维化（CF），作为关键和重叠的特征，杯状细胞增加和粘液分泌过多。由于这些原因，目前的疾病发病机制的范例表明，抑制粘液分泌过多将在这些疾病中具有有益和治疗效果-尽管缺乏强有力的证据来支持人类研究或疾病模型中的这种方法。另一种范例是杯状细胞和粘液是有益的，靶向粘液分泌过多将没有治疗益处，并且实际上可能是有害的策略。在这个高风险，但潜在的范式转变的建议，我们解决这个相对简单的想法。本提案的目的是了解杯状细胞的作用，在维护正常的肺，并在响应气道侮辱和疾病期间的粘液。核心假设是，杯状细胞和粘液是气道防御所必需的，缺乏杯状细胞和粘液将恶化，而不是改善气道疾病的结果。在这些研究中，我们将广泛地提出三个问题：第一，杯状细胞和粘液是维持正常肺所必需的吗？第二，杯状细胞和粘液对气道损伤的反应是否重要？第三，杯状细胞化生/增生和粘液分泌过多对病变肺有益吗？迄今为止，大多数气道研究都是在鼠模型中进行的，由于鼠和人肺之间的重要差异以及缺乏密切模拟人类疾病表型的鼠气道疾病模型，限制了其对人类的适用性。由于猪和人气道/肺生物学非常相似，我们将在猪中进行研究。我们将通过在野生型和CF猪中使用疱疹病毒1型胸苷激酶系统条件性靶向气道杯状细胞来研究杯状细胞和粘液生物学。这项研究提案非常适合新创新者奖计划，因为它挑战了当前的范式，利用了密切模仿人类气道生物学的猪动物模型，并使用了CF猪模型，该模型代表了第一个非鼠动物模型，其中负责人类疾病的基因已被破坏。这些研究具有显著的公共卫生相关性，因为这些发现应该导致新的机制见解和治疗开发，从而对许多人类气道疾病具有很高的潜在影响，包括哮喘、COPD和CF，这些疾病影响近5000万美国人，并且与每年超过450亿美元的医疗保健费用相关。 公共卫生相关性：这项高度创新和潜在的范式转变研究对公共卫生非常重要，因为了解杯状细胞和粘液的作用将对开发新的气道疾病（如COPD，CF和哮喘）治疗干预措施产生关键影响。此外，拟议的研究是密切相关的国家卫生研究院的使命，重点是发现有关疾病的发病机制和翻译这些研究的临床医学。