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（由适用提供）：诸如哮喘和COPD之类的慢性肺部疾病是美国的主要死亡原因之一，也是这些疾病中发生的肺组织进行性重塑的机制。在这些受试者的肺中，腺苷水平升高，其中它与四个受体亚型接合，从而释放促纤维化的细胞因子IL-6，从而增加了对刺激，气道感染和重塑的支气管内的增强。在动物模型中，已知减少腺苷的积累会改变肺部感染的过程并增加生存率。在正常受试者中未观察到哮喘和COPD对腺苷受试者的支气管疗法反应，表明在这些疾病中，支气管痉挛，气道感染和重塑的潜在机制增加了。腺苷是通过在炎症和重塑的部位的ATP去磷酸化以及细胞内产生并通过核侧转运蛋白运输的。在此提案中，我们将生成证据表明，在气道平滑肌中表达的细胞表面蛋白是NAD+的腺苷的重要来源。将NAD+转换为AMP的酶活性涉及CD38，其在气道平滑肌中的表达被炎症和Th2细胞因子增强，并且在更大程度上是从哮喘患者中得出的细胞。这种腺苷和IL-6产生的途径足以引起气道高反应性，气道注入和气道重塑，而与CD38在细胞内钙信号传导和先天免疫力中的作用无关。我们假设在气道平滑肌中抑制CD38表达将通过减少腺苷和IL-6来限制慢性肺疾病的进展。在对炎症环境中的哮喘患者和非肌肉的气道平滑肌细胞的研究中，在慢性过敏原挑战的小鼠模型以及CD38 - / - 小鼠的研究中，我们将提供气道平滑肌作为腺苷和IL-6的重要来源的证据，并旨在靶向NAD++ and+ and and+的inzymes。我们已经确定了两个特定miRNA在CD38表达的调节中的作用，并将证明它们在气道平滑肌细胞中降低腺苷和IL-6释放的能力，以及通过小鼠体内递送气道表型的逆转。