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：
7782703
负责人：
MATHUR S KANNAN
金额：
$ 36.09万
依托单位：
UNIVERSITY OF MINNESOTA
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

来源：
https://reporter.nih.gov/project-details/7782703
关键词：
1-Phosphatidylinositol 3-Kinase 3&apos Untranslated Regions ADP-ribosyl Cyclase Address Agonist Allergens American Asthma Attenuated Binding Bone Marrow Bone Marrow Cells Bronchoalveolar Lavage CCAAT-Enhancer-Binding Proteins Calcium Calcium Signaling Carbachol Cell membrane Cells Cloning Cyclic ADP-Ribose Cytokine Receptors Disease Dose Down-Regulation Elements Exhibits Experimental Models Exposure to Functional disorder GTP-Binding Proteins Genes Glucocorticoids Goals Human Inflammatory Inflammatory Response Interleukin-1 Interleukin-13 Interleukin-4 Investigation Kinetics Knock-out Knockout Mice Laboratories Lung MAPK11 gene Maintenance Mediating Mediator of activation protein Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinases Morbidity - disease rate Mus Muscle Cells Muscle Contraction Muscle function NAADP NADP Ovalbumin Pathogenesis Patients Phenotype Phosphoric Monoester Hydrolases Physiological Prevention Process Proteins Regulation Response Elements Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Sarcoplasmic Reticulum Sequence Analysis Signal Pathway Signal Transduction Smooth Muscle Myocytes Specificity Stimulus Stream TNF gene Tissues Transcript Transcription Factor AP-1 Transcriptional Regulation Transfection Wild Type Mouse airway hyperresponsiveness airway inflammation chemokine cytokine in vivo mRNA Stability methacholine mortality mouse model prevent promoter public health relevance receptor reconstitution respiratory smooth muscle response transcription factor

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，从而导致气道高反应性 (AHR)，这是一个标志这种疾病。炎症细胞因子改变钙信号传导和 ASM 收缩性，导致对激动剂的过度反应。我们实验室的研究提供的证据表明，CD38/环 ADP-核糖信号传导在 ASM 的钙调节中具有核心作用，并且该信号传导途径通过涉及 NF-κB 和 AP-1 的转录机制受到 TH2 和促炎细胞因子的调节。稳定。该调节涉及的信号传导机制是通过 PI3 激酶和丝裂原激活蛋白激酶 (MAPK) 的激活介导的。缺乏 CD38 的小鼠表现出以乙酰甲胆碱反应性减弱为特征的气道表型。这些小鼠的 ASM 细胞对激动剂的钙反应也减少。虽然这些观察结果表明 CD38 与正常气道功能有关，但其在哮喘病理生理学中的潜在作用仍有待确定。在 ASM 细胞中，细胞因子会增强 CD38 的表达，而哮喘治疗的主要药物糖皮质激素会降低这种表达。初步结果表明，CD38 缺陷小鼠在 IL-13 或过敏原致敏和攻击后表现出 AHR 减弱。通过骨髓转移到 CD38 缺陷小鼠体内重建 CD38+/+ 炎症细胞，可恢复对过敏原攻击的 AHR。这些研究首次将 CD38/环 ADP-核糖信号通路与哮喘相关，并为提案中概述的细胞/组织中 CD38 表达的调节机制带来了生理学意义。拟议研究的目标是描绘参与调节 CD38 表达的信号传导机制，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 信号传导以及 NF-κB 和 AP-1 的激活调节 ASM 中 CD38 的表达，并且气道驻留细胞中的 CD38/环 ADP-核糖信号传导足以导致AHR由炎症反应引起。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。在拟议的研究中，我们将确定 ASM 中炎症和 TH2 细胞因子调节 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。这一新信息可能会将 CD38 确定为预防和控制哮喘的潜在药理学靶点。我们建议，气道中 CD38/环 ADP-核糖信号通路的调节剂应该能够防止哮喘等疾病中的气道高反应性。公共卫生相关性。哮喘是一种炎症性疾病，患者气道平滑肌对刺激的反应过度。 IL-13 和 TNFa 等细胞因子在哮喘的发病机制中发挥着核心作用。缺乏 CD38 蛋白的小鼠不会对细胞因子的攻击产生哮喘反应。我们打算研究细胞因子如何调节气道中 CD38 的表达，并确定其在不同哮喘小鼠模型中的作用。这一新信息可能会将 CD38 确定为预防和控制哮喘的潜在药理学靶点。