Adenosine receptors as therapeutic targets for chronic rhinosinusitis

腺苷受体作为慢性鼻窦炎的治疗靶点

• 批准号: 8243944
• 负责人: Xiaoyang Hua
• 金额: $ 18.5万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243944
• 关键词: Adenosine; Affect; Age; Agonist; American; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Attenuated; Biological; Biology; Blood; Breathing; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Cilia; Clinical Data; Complement; Complex; Coughing; Coupled; Defense Mechanisms; Development; Disease; Dissection; Enzymes; Epithelial Cells; Frequencies; Functional disorder; Funding; Genetic; Goals; Homeostasis; Host Defense Mechanism; Human; Human body; Hypersensitivity; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; Investigation; Knowledge; Lead; Lung Inflammation; Mediator of activation protein; Medical; Medicine; Methods; Mucociliary Clearance; Mucous Membrane; Mucous body substance; Mus; Nasal Epithelium; Nasal cavity; Nervous system structure; Neurosecretory Systems; Nose; Nucleosides; Nucleotides; Operative Surgical Procedures; Otolaryngology; Oxygen; Pathogenesis; Patients; Physiological; Physiology; Primary Ciliary Dyskinesias; Process; Purinergic P1 Receptors; Recovery; Regulation; Research; Resolution; Respiratory Failure; Role; Scanning; Signal Pathway; Sinus; Sneezing; Speed; Structure of mucous membrane of nose; Testing; Therapeutic; United States; Work; adenosine deaminase; airway epithelium; airway surface liquid; base; chronic rhinosinusitis; effective therapy; improved; in vivo; new therapeutic target; novel therapeutics; pathogen; pre-clinical; programs; receptor; shear stress; theories; therapeutic target

DESCRIPTION (provided by applicant): Chronic rhinosinusitis (CRS) is a very common upper airway disease affecting more than 31 million Americans. Current therapeutic strategies for CRS include both medical and surgical treatments; one major goal of these treatments is to improve the nasal mucociliary clearance (MCC) function in CRS patients, as this may reverse the diseased sinonasal mucosa to achieve physiological recovery. Adenosine is a ubiquitous nucleoside normally present in the airway lumen and interstitium. Previous in vitro studies have shown that adenosine is the major regulator for nasal airway surface liquid homeostasis. It can also increase cilia beating frequency of cultured human nasal epithelium. In our preliminary in vivo studies, a potent effect of adenosine, but not ATP, to accelerate nasal MCC was also observed. These findings indicate that adenosine and its receptors may be of great therapeutic value for CRS by speeding up nasal MCC. In addition to regulating MCC, adenosine has also been shown to elicit both anti- and pro-inflammatory effects. Although previous studies in the lower airways have revealed that adenosine enhances inflammation, our preliminary studies have shown that adenosine is not pro-inflammatory in the nose and sinuses. Based on all of these findings, we hypothesize that adenosine is the key factor to enhance the nasal MCC in vivo (Aim 1) and its anti-inflammatory actions will attenuate the development of CRS (Aim 2). The effect of adenosine on nasal MCC will be tested in vivo at both healthy and inflamed nose and sinuses. The underlying mechanisms will be determined at both in vivo and in vitro levels. The role of adenosine and adenosine receptors in CRS development, progression, and resolution will also be examined. We believe that the completion of this translational project will lead to a novel therapeutic strategy for CRS. It will also be of great significance to enhancing our knowledge of adenosine airway biology and re-evaluating the unified airway theory. PUBLIC HEALTH RELEVANCE: Chronic rhinosinusitis (CRS) is a very common inflammatory disease in the nose and sinuses. Currently, both medical and surgical therapies are used for CRS patients; however, many patients still present with persistent inflammation even after aggressive treatment. In the proposed studies, we will examine the role of adenosine, a common mediator in human body, and its receptors, in CRS development, and explore the therapeutic value of targeting adenosine receptors for the treatment of CRS.

描述（由申请人提供）：慢性鼻塞炎（CRS）是一种非常常见的上呼吸道疾病，影响了超过3100万美国人。 CRS的当前治疗策略包括医学和外科治疗；这些治疗方法的一个主要目标是改善CRS患者的鼻粘膜清除率（MCC）功能，因为这可能会扭转患病的鼻窦粘膜以实现生理康复。腺苷是一种普通的核苷，通常存在于气道管腔和间质中。以前的体外研究表明，腺苷是鼻气道表面液体稳态的主要调节剂。它还可以增加纤毛的培养人鼻上皮的频率。在我们的初步体内研究中，还观察到腺苷（而不是ATP）加速鼻腔MCC的有效作用。这些发现表明，腺苷及其受体通过加快鼻腔MCC而对CRS具有很高的治疗价值。除了调节MCC外，还显示腺苷还引起抗炎作用。尽管先前在下部气道中的研究表明腺苷会增强炎症，但我们的初步研究表明，腺苷在鼻子和鼻窦上不是促炎。基于所有这些发现，我们假设腺苷是增强体内鼻腔MCC的关键因素（AIM 1），其抗炎作用将减轻CRS的发展（AIM 2）。腺苷对鼻MCC的影响将在健康和发炎的鼻子和鼻窦下在体内进行测试。基本机制将在体内和体外水平上确定。还将研究腺苷和腺苷受体在CR的发育，进展和分辨率中的作用。我们认为，这个翻译项目的完成将导致CRS的新型治疗策略。 It will also be of great significance to enhancing our knowledge of adenosine airway biology and re-evaluating the unified airway theory. 公共卫生相关性：慢性鼻 - CRS（CRS）是鼻子和鼻窦中非常常见的炎症性疾病。目前，医疗和手术疗法均用于CRS患者；但是，即使在积极治疗后，许多患者仍然存在持续的炎症。在拟议的研究中，我们将研究腺苷（人体中常见的介体）及其受体在CRS发育中的作用，并探索靶向腺苷受体治疗CRS的治疗价值。