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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

基本信息

批准号：
9242566
负责人：
MATHUR S KANNAN
金额：
$ 19.08万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242566
关键词：
1-Phosphatidylinositol 3-Kinase 3&apos Untranslated Regions Address Adenosine Adenosine A2B Receptor Adenosine Diphosphate Ribose Adverse effects Affinity Allergens Allergic inflammation Alpha Cell Animal Model Asthma Binding Bone Marrow Bronchial Spasm Bronchoalveolar Lavage Bronchoconstriction Bypass Calcium Calcium Signaling Cause of Death Cell Surface Proteins Cell surface Cells Chronic Chronic Obstructive Airway Disease Chronic lung disease Clinical Trials Cyclic ADP-Ribose Disease Enzymes G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Generations Genes Genetic Growth Factor Health Care Costs Human Hydrolase IL5 gene Inflammation Inflammatory Interleukin-13 Interleukin-4 Interleukin-6 Intracellular Transport Laboratories Lead Lung Lung Inflammation Mediating Mediator of activation protein Metabolism MicroRNAs Mitogen-Activated Protein Kinase Kinases Molecular Mus Muscle Cells NAADP Natural Immunity Nucleoside Transporter Pathogenesis Pathway interactions Periodicity Pharmaceutical Preparations Phenotype Play Production Protein Dephosphorylation Proteins Pulmonary Pathology Purinergic P1 Receptors Pyroglyphidae Regulation Role Signal Transduction Site Small Interfering RNA Source Stimulus Structure of parenchyma of lung Testing Therapeutic Intervention Tissues airway hyperresponsiveness airway inflammation airway remodeling arm asthmatic asthmatic airway attenuation chemokine cytokine enzyme activity extracellular in vivo inflammatory milieu knock-down mouse model novel plasma cell membrane glycoprotein PC-1 public health relevance receptor receptor density respiratory smooth muscle response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Chronic lung diseases such as asthma and COPD are one of the leading causes of death in the US and the mechanisms for the progressive remodeling of lung tissue that occurs in these diseases are incompletely understood. Adenosine levels are elevated in the lungs of these subjects where it engages four subtypes of receptors which results in the release of the pro-fibrotic cytokine IL-6, leading to augmented bronchoconstriction to stimuli, airway inflammation and remodeling. In animal models, decreasing the accumulation of adenosine is known to alter the course of lung inflammation and increase survival. The bronchospastic response in subjects with asthma and COPD to adenosine is not seen in normal subjects, indicating that the underlying mechanisms of increased bronchospasm, airway inflammation and remodeling are augmented in these diseases. Adenosine is generated by dephosphorylation of ATP at sites of inflammation and remodeling as well as generated intracellularly and transported through the nucleoside transporters. In this proposal, we will generate evidence that CD38, a cell surface protein expressed in airway smooth muscle, is a significant source of adenosine from NAD+ by the enzymatic cascade CD38/CD203a/CD73. The enzymatic activity that converts NAD+ to AMP involves CD38 whose expression in airway smooth muscle is augmented by inflammatory and Th2 cytokines and to a greater extent in cells derived from asthmatics. This pathway of adenosine and IL-6 production are sufficient to cause airway hyperresponsiveness, airway inflammation and airway remodeling independent of the roles of CD38 in intracellular calcium signaling and innate immunity. Thus we postulate that inhibiting CD38 expression in airway smooth muscle will limit the progression of chronic lung diseases by decreasing adenosine and IL-6. In the studies with airway smooth muscle cells from asthmatics and non-asthmatics maintained in an inflammatory environment, in a mouse model of chronic allergen challenge and in the Cd38-/- mice, we will provide evidence for airway smooth muscle as a significant source of adenosine and IL-6 and that targeting the enzymes involved in the conversion of NAD+ to adenosine can reverse the lung damage. We have identified the roles of two specific miRNAs in the regulation of CD38 expression and will demonstrate their ability to decrease adenosine and IL-6 release in airway smooth muscle cells and reversal of the airway phenotype by delivering in vivo in mice.

描述（由申请人提供）：哮喘和慢性阻塞性肺病等慢性肺部疾病是美国的主要原因之一，并且这些疾病中发生的肺组织逐渐重塑的机制尚不完全清楚。这些受试者肺部的腺苷水平升高，腺苷与四种受体亚型结合，导致促纤维化细胞因子 IL-6 的释放，导致支气管收缩加剧，从而刺激气道炎症和重塑。在动物模型中，已知减少腺苷的积累可以改变肺部炎症的进程并提高生存率。哮喘和慢性阻塞性肺病患者对腺苷的支气管痉挛反应在正常受试者中没有观察到，这表明支气管痉挛增加、气道炎症和重塑的潜在机制在这些疾病中增强。腺苷由炎症和重塑部位的 ATP 去磷酸化产生，并在细胞内产生并通过核苷转运蛋白转运。在本提案中，我们将提供证据证明 CD38（一种在气道平滑肌中表达的细胞表面蛋白）是通过酶级联 CD38/CD203a/CD73 从 NAD+ 产生腺苷的重要来源。将 NAD+ 转化为 AMP 的酶活性涉及 CD38，CD38 在气道平滑肌中的表达会因炎症和 Th2 细胞因子而增强，在哮喘细胞中的表达也会增强。这种腺苷和 IL-6 产生途径足以引起气道高反应性、气道炎症和气道重塑，而与 CD38 在细胞内钙信号传导和先天免疫中的作用无关。因此，我们推测抑制气道平滑肌中 CD38 的表达将通过减少腺苷和 IL-6 来限制慢性肺病的进展。在对来自哮喘患者和非哮喘患者的气道平滑肌细胞维持在炎症环境中、在慢性过敏原激发的小鼠模型和 Cd38-/- 小鼠中进行的研究中，我们将提供证据证明气道平滑肌是腺苷和 IL-6 的重要来源，并且针对参与 NAD+ 转化为腺苷的酶可以逆转肺损伤。我们已经确定了两种特定 miRNA 在调节 CD38 表达中的作用，并将证明它们能够减少气道平滑肌细胞中腺苷和 IL-6 的释放，并通过在小鼠体内递送来逆转气道表型。