The Role of Caveolins in Lung Inflammation

小窝蛋白在肺部炎症中的作用

基本信息

  • 批准号:
    8052729
  • 负责人:
  • 金额:
    $ 34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-04-01 至 2014-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Exaggerated airway narrowing and inflammation are hallmarks of clinically-important diseases such as asthma. Airway tone, largely determined by intracellular Ca2+ ([Ca2+]i) (mediated by Ca2+ influx and sarcoplasmic (SR) Ca2+ release) and Ca2+ sensitivity for force generation of airway smooth muscle (ASM), is enhanced by pro-inflammatory cytokines such as TNFa. In this regard, the role of caveolae and caveolins in the lung is an exciting and emerging area of research. Caveolae are small, uncoated flask-shaped invaginations of the plasma membrane (PM) of most cell types, and contain structural proteins called caveolins (caveolin-1, -2 and/or -3). Recent studies including our own have demonstrated that normal human ASM expresses caveolae and caveolin-1, with specific proteins involved in [Ca2+]i and force regulation co-localizing with caveolin-1. Preliminary studies show that airway inflammation (either in vitro following TNFa exposure or in vivo in a mouse model) increases caveolin-1 expression and enhances caveolar regulation of ASM contractility, suggesting that overall, caveolin-1 is associated with or promotes ASM contractility. The long term goal of the proposed studies is to understand the mechanisms by which caveolae and caveolins regulate ASM contractility under normal conditions and with airway disease. Ca2+ The overall hypothesis is that caveolae facilitate PM- SR interactions, thus influencing [Ca2+]i and force in ASM. In addition, we hypothesize that airway inflammation increases caveolae and caveolin-1 expression, and thus enhances PM-SR interactions, leading to increased [Ca2+]i and force in ASM. The novelty of our studies lies in linking previous anatomical and biochemical evidence for caveolin-1 in ASM to a physiological role in regulation of ASM contractility. Overall Approach: In vitro studies with human ASM cells and tissues in Aim 1 will examine mechanisms that can be modulated by caveolin-1 with agonist (ACh) stimulation under normal conditions, focusing on agonist receptors, second messengers (PLC/IP3, cADPR), regulation of store-operated Ca2+ entry (SOCE) by (STIM1/Orai1), and RhoA (Ca2+ sensitization). Mechanisms underlying altered caveolin-1 expression (Aim 2) and caveolin-1 contribution to enhanced ASM contractility (Aim 3) with inflammation (induced by TNFa) will then be examined, focusing on specific mechanisms (TNFR1, PTRF, MAPK, NF-?B). Finally in Aim 4, in vitro data will be integrated at the in vivo level using an ovalbumin (OVA) model of airway hyperresponsiveness in wildtype (WT) and caveolin-1 knockout (KO) mice. The Specific Aims of this proposal are: 1) To determine mechanisms by which caveolae/caveolin-1 regulate [Ca2+]i and force responses of human ASM to agonist 2 ) To determine mechanisms by which cytokine (TNFa) stimulation alters caveolin-1 expression in human ASM 3) To determine the mechanisms by which caveolin-1 contributes to TNFa-induced enhancement of [Ca2+]i and force in human ASM; 4) To determine the role of caveolin-1 in airway hyperresponsiveness in vivo. PUBLIC HEALTH RELEVANCE: There is increasing recognition that abnormalities in airway smooth muscle contractility (exacerbated by inflammation) contribute to exaggerated airway narrowing and accompanying shortness of breath in clinically- important diseases such as asthma and chronic bronchitis. In this regard, the potential role of cellular structures called caveolae and their constituent caveolin proteins in regulation of airway contractility is an exciting and emerging area of research. By establishing the role of caveolae and caveolins in airway narrowing with or without inflammation, the proposed studies will the foundation for better understanding of airway diseases, and potential development of new therapeutic targets.
描述(由申请人提供):过度的气道狭窄和炎症是临床重要疾病(如哮喘)的标志。气道张力主要由细胞内Ca 2+([Ca 2 +]i)(由Ca 2+内流和肌浆(SR)Ca 2+释放介导)和气道平滑肌(ASM)的力产生的Ca 2+敏感性决定,通过促炎细胞因子如TNF α增强。在这方面,小窝和小窝蛋白在肺中的作用是一个令人兴奋的新兴研究领域。小窝是大多数细胞类型的质膜(PM)的小的、未涂覆的瓶状内陷,并且含有称为小窝蛋白(小窝蛋白-1、-2和/或-3)的结构蛋白。最近的研究表明,包括我们自己的研究表明,正常人ASM表达小窝和小窝蛋白-1,与特定的蛋白参与[Ca 2 +]i和力调节共定位与小窝蛋白-1。初步研究显示,气道炎症(在TNF α暴露后的体外或在小鼠模型中的体内)增加小窝蛋白-1表达并增强ASM收缩性的小窝调节,表明总体上,小窝蛋白-1与ASM收缩性相关或促进ASM收缩性。这些研究的长期目标是了解在正常情况下和气道疾病时,小窝和小窝蛋白调节ASM收缩性的机制。Ca ~(2+)总体假设是小窝促进PM-SR相互作用,从而影响ASM中的[Ca ~(2+)]i和力。此外,我们假设气道炎症增加了小窝和小窝蛋白-1的表达,从而增强了PM-SR相互作用,导致ASM中[Ca 2 +]i和力增加。我们的研究的新奇在于连接以前的解剖学和生物化学的证据,小窝蛋白-1在ASM的生理作用,调节ASM收缩。总体方法:目标1中的人ASM细胞和组织的体外研究将检查在正常条件下可通过小窝蛋白-1与激动剂(ACh)刺激进行调节的机制,重点是激动剂受体、第二信使(PLC/IP 3、cADPR)、(STIM 1/Orai 1)对钙库操纵的钙内流(SOCE)的调节和RhoA(钙致敏)。然后将研究改变小窝蛋白-1表达(Aim 2)和小窝蛋白-1对增强ASM收缩性(Aim 3)与炎症(由TNF α诱导)的贡献的潜在机制,重点关注特定机制(TNFR 1、PTRF、MAPK、NF-?B)。最后,在目的4中,将在野生型(WT)和小窝蛋白-1敲除(KO)小鼠中使用气道高反应性的卵清蛋白(OVA)模型在体内水平整合体外数据。本研究的具体目的是:1)确定caveolae/caveolin-1调节人ASM对激动剂的[Ca ~(2+)]i和力反应的机制2)确定细胞因子(TNF α)刺激改变人ASM中caveolin-1表达的机制3)确定caveolin-1促进TNF α诱导的人ASM中[Ca ~(2+)]i和力的增强的机制; 4)研究caveolin-1在气道高反应性中的作用。公共卫生相关性:越来越多的人认识到气道平滑肌收缩性的异常(由炎症加剧)会导致过度的气道狭窄并伴随临床上重要的疾病如哮喘和慢性支气管炎中的呼吸短促。在这方面,称为小窝的细胞结构及其组成小窝蛋白在调节气道收缩性中的潜在作用是一个令人兴奋的新兴研究领域。通过建立小窝和小窝蛋白在有或无炎症的气道狭窄中的作用,所提出的研究将为更好地理解气道疾病和潜在的新的治疗靶点的开发奠定基础。

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 }}

Christina Maria Pabelick其他文献

Christina Maria Pabelick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('Christina Maria Pabelick', 18)}}的其他基金

Hydrogen Sulfide in Neonatal Airway Disease
新生儿气道疾病中的硫化氢
  • 批准号:
    10603293
  • 财政年份:
    2023
  • 资助金额:
    $ 34万
  • 项目类别:
Nicotine, Airway Smooth Muscle and Asthma
尼古丁、气道平滑肌和哮喘
  • 批准号:
    9763806
  • 财政年份:
    2019
  • 资助金额:
    $ 34万
  • 项目类别:
Nicotine, Airway Smooth Muscle and Asthma
尼古丁、气道平滑肌和哮喘
  • 批准号:
    10441276
  • 财政年份:
    2019
  • 资助金额:
    $ 34万
  • 项目类别:
Nicotine, Airway Smooth Muscle and Asthma
尼古丁、气道平滑肌和哮喘
  • 批准号:
    10179451
  • 财政年份:
    2019
  • 资助金额:
    $ 34万
  • 项目类别:
The Role of Caveolins in Lung Inflammation
小窝蛋白在肺部炎症中的作用
  • 批准号:
    8431776
  • 财政年份:
    2009
  • 资助金额:
    $ 34万
  • 项目类别:
The Role of Caveolins in Lung Inflammation
小窝蛋白在肺部炎症中的作用
  • 批准号:
    7791431
  • 财政年份:
    2009
  • 资助金额:
    $ 34万
  • 项目类别:
The Role of Caveolins in Lung Inflammation
小窝蛋白在肺部炎症中的作用
  • 批准号:
    8235009
  • 财政年份:
    2009
  • 资助金额:
    $ 34万
  • 项目类别:
The Role of Caveolins in Lung Inflammation
小窝蛋白在肺部炎症中的作用
  • 批准号:
    7645490
  • 财政年份:
    2009
  • 资助金额:
    $ 34万
  • 项目类别:
The Role of Caveolins in Lung Inflammation
小窝蛋白在肺部炎症中的作用
  • 批准号:
    7841086
  • 财政年份:
    2009
  • 资助金额:
    $ 34万
  • 项目类别:
The Role of Caveolins in Lung Inflammation
小窝蛋白在肺部炎症中的作用
  • 批准号:
    7822359
  • 财政年份:
    2009
  • 资助金额:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 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:
    $ 34万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了