Airway Goblet Cells: Friend or Foe?

气道杯状细胞:朋友还是敌人?

基本信息

  • 批准号:
    8355114
  • 负责人:
  • 金额:
    $ 226.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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,在这一肺防御第一线中的作用目前尚不清楚,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。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

DAVID A STOLTZ其他文献

FATAL LUNG INJURY SECONDARY TO TRIMETHOPRIM-SULFAMETHOXAZOLE
  • DOI:
    10.1016/j.chest.2023.07.1615
  • 发表时间:
    2023-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    HALEY PYSICK;DAVID A STOLTZ
  • 通讯作者:
    DAVID A STOLTZ

DAVID A STOLTZ的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('DAVID A STOLTZ', 18)}}的其他基金

Climate Change and Lung Health Training Program
气候变化与肺部健康培训计划
  • 批准号:
    10556149
  • 财政年份:
    2023
  • 资助金额:
    $ 226.5万
  • 项目类别:
Testing the Contributions of Airway Submucosal Glands and Surface Epithelia to Lung Health
测试气道粘膜下腺和表面上皮对肺部健康的贡献
  • 批准号:
    10597111
  • 财政年份:
    2022
  • 资助金额:
    $ 226.5万
  • 项目类别:
Animal Models Core
动物模型核心
  • 批准号:
    10677590
  • 财政年份:
    2020
  • 资助金额:
    $ 226.5万
  • 项目类别:
Animal Models Core
动物模型核心
  • 批准号:
    10024664
  • 财政年份:
    2020
  • 资助金额:
    $ 226.5万
  • 项目类别:
Animal Models Core
动物模型核心
  • 批准号:
    10248526
  • 财政年份:
    2020
  • 资助金额:
    $ 226.5万
  • 项目类别:
Animal Models Core
动物模型核心
  • 批准号:
    10470334
  • 财政年份:
    2020
  • 资助金额:
    $ 226.5万
  • 项目类别:
Airway Alkalinization and Repurposing Tromethamine as a Therapeutic Approach in Cystic Fibrosis
气道碱化和重新利用氨丁三醇作为囊性纤维化的治疗方法
  • 批准号:
    10155587
  • 财政年份:
    2017
  • 资助金额:
    $ 226.5万
  • 项目类别:
Airway Alkalinization and Repurposing Tromethamine as a Therapeutic Approach in Cystic Fibrosis
气道碱化和重新利用氨丁三醇作为囊性纤维化的治疗方法
  • 批准号:
    9289053
  • 财政年份:
    2017
  • 资助金额:
    $ 226.5万
  • 项目类别:
Airway Alkalinization and Repurposing Tromethamine as a Therapeutic Approach in Cystic Fibrosis
气道碱化和重新利用氨丁三醇作为囊性纤维化的治疗方法
  • 批准号:
    9918957
  • 财政年份:
    2017
  • 资助金额:
    $ 226.5万
  • 项目类别:
Paraoxonase-2 S311C Polymorphism Alters Glycosylation and Lactonase Activity
Paraoxonase-2 S311C 多态性改变糖基化和内酯酶活性
  • 批准号:
    8110743
  • 财政年份:
    2010
  • 资助金额:
    $ 226.5万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 226.5万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了