Adenosine receptors as therapeutic targets for chronic rhinosinusitis

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和手术治疗;这些治疗的一个主要目标是改善CRS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气道中。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。能增加培养的人鼻粘膜上皮细胞纤毛的搏动频率。在我们的初步体内研究中，还观察到腺苷而非ATP加速鼻MCC的有效作用。提示腺苷及其受体可能通过加速鼻粘膜的MCC而对CRS具有重要的治疗价值。除了调节MCC之外，腺苷还显示出引起抗炎和促炎作用。虽然以前在下呼吸道的研究表明，腺苷增强炎症，我们的初步研究表明，腺苷是不是在鼻子和鼻窦促炎。基于所有这些发现，我们假设腺苷是增强体内鼻MCC的关键因素（目的1），其抗炎作用将减弱CRS的发展（目的2）。腺苷对鼻MCC的作用将在健康和发炎的鼻和鼻窦中进行体内测试。将在体内和体外水平确定潜在的机制。腺苷和腺苷受体在CRS发展、进展和消退中的作用也将被研究。我们相信，这个翻译项目的完成将导致一个新的治疗策略CRS。这对于提高我们对腺苷气道生物学的认识和重新评价气道统一理论具有重要意义。 公共卫生相关性：慢性鼻窦炎（CRS）是一种非常常见的鼻和鼻窦炎性疾病。目前，药物和手术治疗都用于CRS患者;然而，即使在积极治疗后，许多患者仍然存在持续性炎症。在拟议的研究中，我们将检查腺苷（人体内的常见介质）及其受体在CRS发展中的作用，并探索靶向腺苷受体治疗CRS的治疗价值。

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.