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: 8415507
• 负责人: STEPHEN Lloyd TILLEY
• 金额: $ 22.2万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415507
• 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.

描述（由申请人提供）：慢性鼻窦炎 (CRS) 是一种非常常见的上呼吸道疾病，影响超过 3100 万美国人。目前CRS的治疗策略包括药物治疗和手术治疗；这些治疗的一个主要目标是改善慢性鼻窦炎患者的鼻粘膜纤毛清除（MCC）功能，因为这可能逆转患病的鼻窦粘膜以实现生理恢复。腺苷是一种普遍存在的核苷，通常存在于气道腔和间质中。先前的体外研究表明，腺苷是鼻气道表面液体稳态的主要调节剂。它还可以增加培养的人鼻上皮的纤毛跳动频率。在我们的初步体内研究中，还观察到腺苷（而非 ATP）对加速鼻 MCC 具有有效作用。这些发现表明，腺苷及其受体可能通过加速鼻 MCC 对 CRS 具有巨大的治疗价值。除了调节 MCC 之外，腺苷还被证明具有抗炎和促炎作用。尽管之前对下呼吸道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中并不促炎。基于所有这些发现，我们假设腺苷是体内增强鼻 MCC 的关键因素（目标 1），其抗炎作用将减弱 CRS 的发展（目标 2）。腺苷对鼻 MCC 的影响将在健康和发炎的鼻子和鼻窦中进行体内测试。潜在的机制将在体内和体外水平上确定。腺苷和腺苷受体在 CRS 发生、进展和缓解中的作用也将得到研究。我们相信，这个转化项目的完成将为 CRS 带来一种新的治疗策略。这对于提高我们对腺苷气道生物学的认识、重新评价统一气道理论也具有重要意义。