Adenosine receptors as therapeutic targets for chronic rhinosinusitis

腺苷受体作为慢性鼻窦炎的治疗靶点

基本信息

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
项目类别：
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

项目摘要

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。这对于增强我们对腺苷气道生物学的了解并重新评估统一气道理论也将具有重要意义。