Airway Goblet Cells: Friend or Foe?

描述(由申请人提供) 摘要：肺部健康严重依赖于维持接近无菌的呼吸道，这是一个涉及粘液产生、呼吸道抗菌因子和粘液纤毛清除的过程。高脚杯细胞是一种特殊的呼吸道细胞，它在这一肺防御第一线中的作用尚不清楚，S。此外，最常见的肺部疾病，以及与发病率和死亡率最高的疾病相关的疾病，包括哮喘、慢性阻塞性肺疾病(COPD)和囊性纤维化(CF)，其关键和重叠的特征是杯状细胞和粘液高分泌。出于这些原因，目前的疾病发病机制范式表明，抑制粘液高分泌将对这些疾病具有有益和治疗效果--尽管在人类研究或疾病模型中缺乏强有力的证据支持这一方法。另一种范式是，杯状细胞和粘液是有益的，而以粘液高分泌为靶点将没有治疗益处，实际上可能是一种有害的策略。在这个高风险，但可能会改变范式的建议中，我们讨论了这个相对简单的想法。这项建议的目的是了解杯状细胞作为粘液在维持正常肺以及对呼吸道损伤和疾病期间的反应中所起的作用。核心假设是，杯状细胞和黏液是呼吸道防御所必需的，缺乏杯状细胞和黏液将恶化而不是改善呼吸道疾病的结局。在这些研究中，我们将大致提出三个问题：第一，维持正常的肺是否需要杯状细胞和粘液？其次，杯状细胞和粘液对呼吸道损伤的反应重要吗？第三，杯状细胞化生/增生和粘液高分泌对病变肺有好处吗？到目前为止，大多数呼吸道研究都是在小鼠模型中进行的，由于小鼠和人类肺之间的重要差异，以及缺乏密切模拟人类疾病表型的小鼠呼吸道疾病模型，因此限制了它们对人类的适用性。由于猪和人类的呼吸道/肺部生物学非常相似，我们将在猪身上进行研究。我们将通过用疱疹病毒1型胸苷激酶系统有条件地靶向野生型和CF猪的气道杯细胞来研究杯状细胞和粘液生物学。这项研究建议非常适合新创新者奖计划，因为它挑战了当前的范式，利用了密切模拟人类呼吸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导致人类疾病的基因被干扰的非小鼠动物模型。这些研究具有重大的公共卫生相关性，因为这些发现将导致新的机制洞察和治疗开发，从而对许多人类呼吸道疾病产生高度潜在的影响，包括哮喘、COPD和CF，这些疾病影响着近5000万美国人，每年与超过450亿美元的医疗费用相关。 公共卫生相关性：这项具有高度创新性和潜在范式转变的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针对COPD、CF和哮喘等呼吸道疾病的新治疗干预措施具有关键影响。此外，拟议的研究与NIH的使命密切相关，专注于与疾病发病机制相关的发现，并将这些研究转化为临床医学。

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.