Adenosine receptors as therapeutic targets for chronic rhinosinusitis

描述(申请人提供)：慢性鼻-鼻窦炎(CRS)是一种非常常见的上呼吸道疾病，影响着3100多万美国人。目前CRS的治疗策略包括内科治疗和手术治疗，这些治疗的主要目的之一是改善CRS患者的鼻黏膜纤毛清除(MCC)功能，因为这可能会逆转病变的鼻窦黏膜，实现生理性恢复。腺苷是一种普遍存在的核苷，通常存在于气道腔和间质中。以往的体外研究表明，腺苷是鼻呼吸道表面液体稳态的主要调节因子。并能提高培养的人鼻上皮纤毛搏动频率。在我们的初步活体研究中，还观察到腺苷对鼻微血管细胞癌有促进作用，而不是三磷酸腺苷。提示腺苷及其受体可能通过加速鼻腔MCC而对CRS具有重要的治疗价值。除了调节MCC外，腺苷还被证明具有抗炎和促炎作用。虽然先前在下呼吸道的研究表明腺苷可以增强炎症，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部微循环的关键因素(目标1)，其抗炎作用将减缓CRS的发展(目标2)。腺苷对鼻腔MCC的影响将在健康和发炎的鼻子和鼻窦中进行活体测试。潜在的机制将在体内和体外两个水平上确定。腺苷和腺苷受体在CRS的发生、发展和分解中的作用也将被研究。我们相信，这一翻译项目的完成将为CRS带来一种新的治疗策略。这对增进我们对腺苷呼吸道生物学的认识，重新评价统一的气道理论也具有重要意义。

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.