Dynamic Calcium Regulation in Airway Smooth Muscle

气道平滑肌的动态钙调节

基本信息

  • 批准号:
    7588782
  • 负责人:
  • 金额:
    $ 36.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-04-01 至 2012-02-29
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Asthma is an inflammatory disease in which TH2 (such as IL-13) and proinflammatory (such as TNFa) cytokines induce abnormalities of airway smooth muscle (ASM) function that causes airway hyperresponsiveness (AHR), a hallmark of this disease. Inflammatory cytokines alter calcium signaling and contractility of ASM which results in hyperreactivity to agonists. Investigations from our laboratory have provided evidence that the CD38/Cyclic ADP-ribose signaling has a central role in calcium regulation in ASM and this signaling pathway is regulated by TH2 and proinflammatory cytokines through transcriptional mechanisms involving NF-?B and AP-1 and transcript stability. The signaling mechanisms involved in this regulation are mediated by activation of PI3 kinases and Mitogen-activated Protein Kinases (MAPK). Mice deficient in CD38 exhibit an airway phenotype characterized by attenuated methacholine responsiveness. ASM cells from these mice also have reduced calcium responses to agonists. While these observations implicate CD38 in normal airway function, its potential role in the pathophysiology of asthma remains to be determined. In ASM cells, CD38 expression is augmented by cytokines, and glucocorticoids, a mainstay of asthma therapy, decrease this expression. Preliminary results reveal that CD38 deficient mice exhibit attenuated AHR following IL-13 or allergen sensitization and challenge. Reconstitution of CD38+/+ inflammatory cells by bone marrow transfer into CD38 deficient mice restores AHR to allergen challenge. These studies are the first to implicate the CD38/Cyclic ADP-ribose signaling pathway in asthma and bring a physiological significance of the mechanisms of regulation of CD38 expression in cells/tissues outlined in the proposal. The goal of the proposed studies is to delineate the signaling mechanisms involved in the regulation of CD38 expression and to define the role of CD38 in airway smooth muscle cells and inflammatory cells in AHR. The overall hypothesis is that cytokines regulate CD38 expression in ASM through PI3 kinase activation, down-stream MAPK signaling and activation of NF-?B and AP-1, and that the CD38/Cyclic ADP-ribose signaling in airway resident cells is sufficient to cause AHR resulting from the inflammatory response. Glucocorticoid effects are mediated through inhibition of MAPK and transcription factor activation, and transcript stability. In the proposed studies, we will determine specific mechanisms of CD38 regulation by inflammatory and TH2 cytokines in ASM and the in vivo significance of these mechanisms in mouse models of experimental asthma. This new information may identify CD38 as a potential pharmacological target in the prevention and control of asthma. We propose that modulators of the CD38/Cyclic ADP-ribose signaling pathway in the airways should afford protection from airway hyperresponsiveness in diseases such as asthma. PUBLIC HEALTH RELEVANCE. Asthma is an inflammatory disease in which patients have exaggerated airway smooth muscle response to stimuli. Cytokines such as IL-13 and TNFa have a central role in the pathogenesis of asthma. Mice deficient in a protein, CD38, do not develop an asthmatic response to challenges with cytokines. We are proposing to study how the expression of CD38 in the airways is regulated by cytokines and establish its role in different mouse models of asthma. This new information may identify CD38 as a potential pharmacological target in the prevention and control of asthma.
描述(由申请人提供):哮喘是一种炎症性疾病,其中TH2(如IL-13)和促炎细胞因子(如TNFa)诱导气道平滑肌(ASM)功能异常,导致气道高反应性(AHR),这是该疾病的一个标志。炎症细胞因子改变钙信号和ASM的收缩性,从而导致对激动剂的高反应性。我们实验室的研究提供了证据,证明CD38/环adp核糖信号通路在ASM的钙调节中起核心作用,并且该信号通路受TH2和促炎细胞因子通过NF-?B和AP-1以及转录物稳定性。参与这一调控的信号机制是由PI3激酶和丝裂原活化蛋白激酶(MAPK)的激活介导的。缺乏CD38的小鼠表现出以甲胆碱反应性减弱为特征的气道表型。来自这些小鼠的ASM细胞对激动剂的钙反应也降低。虽然这些观察结果暗示CD38与正常气道功能有关,但其在哮喘病理生理中的潜在作用仍有待确定。在ASM细胞中,细胞因子可增强CD38的表达,而糖皮质激素(哮喘治疗的主要药物)可降低这种表达。初步结果显示CD38缺陷小鼠在IL-13或过敏原致敏和刺激后AHR减弱。通过骨髓移植重建CD38+/+炎症细胞,使CD38缺陷小鼠恢复AHR对过敏原的攻击。这些研究首次揭示了CD38/环adp核糖信号通路在哮喘中的作用,并为本文提出的细胞/组织中CD38表达调控机制提供了生理学意义。本研究的目的是描述参与调节CD38表达的信号机制,并确定CD38在AHR中气道平滑肌细胞和炎症细胞中的作用。总体假设是细胞因子通过PI3激酶激活、下游MAPK信号传导和NF-?B和AP-1,并且气道驻留细胞中的CD38/环adp核糖信号足以引起炎症反应引起的AHR。糖皮质激素的作用是通过抑制MAPK和转录因子激活以及转录稳定性来介导的。在拟开展的研究中,我们将确定炎症和TH2细胞因子在ASM中调控CD38的具体机制,以及这些机制在实验性哮喘小鼠模型中的体内意义。这一新信息可能确定CD38作为预防和控制哮喘的潜在药理学靶点。我们提出气道中CD38/环adp核糖信号通路的调节剂可以保护气道免受哮喘等疾病的高反应性。公共卫生相关性。哮喘是一种炎症性疾病,患者对刺激有过度的气道平滑肌反应。细胞因子如IL-13和TNFa在哮喘的发病机制中起核心作用。缺乏CD38蛋白的小鼠对细胞因子的挑战不会产生哮喘反应。我们建议研究细胞因子如何调节气道中CD38的表达,并确定其在不同小鼠哮喘模型中的作用。这一新信息可能确定CD38作为预防和控制哮喘的潜在药理学靶点。

项目成果

期刊论文数量(0)
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MATHUR S KANNAN其他文献

MATHUR S KANNAN的其他文献

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{{ truncateString('MATHUR S KANNAN', 18)}}的其他基金

MicroRNA regulation of CD38 and chemokine genes in human airway smooth muscle
MicroRNA对人气道平滑肌CD38和趋化因子基因的调控
  • 批准号:
    9242566
  • 财政年份:
    2016
  • 资助金额:
    $ 36.09万
  • 项目类别:
DYNAMIC CALCIUM REGULATION IN AIRWAY SMOOTH MUSCLE
气道平滑肌的动态钙调节
  • 批准号:
    2901276
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:
Dynamic Calcium Regulation in Airway Smooth Muscle
气道平滑肌的动态钙调节
  • 批准号:
    6832227
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:
DYNAMIC CALCIUM REGULATION IN AIRWAY SMOOTH MUSCLE
气道平滑肌的动态钙调节
  • 批准号:
    2633006
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:
Dynamic Calcium Regulation in Airway Smooth Muscle
气道平滑肌的动态钙调节
  • 批准号:
    8039269
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:
Dynamic Calcium Regulation in Airway Smooth Muscle
气道平滑肌的动态钙调节
  • 批准号:
    6982830
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:
Dynamic Calcium Regulation in Airway Smooth Muscle
气道平滑肌的动态钙调节
  • 批准号:
    7149163
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:
Dynamic Calcium Regulation in Airway Smooth Muscle
气道平滑肌的动态钙调节
  • 批准号:
    7460123
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:
DYNAMIC CALCIUM REGULATION IN AIRWAY SMOOTH MUSCLE
气道平滑肌的动态钙调节
  • 批准号:
    6183833
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:
Dynamic Calcium Regulation in Airway Smooth Muscle
气道平滑肌的动态钙调节
  • 批准号:
    6724027
  • 财政年份:
    1998
  • 资助金额:
    $ 36.09万
  • 项目类别:

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