Endogenous Cannabinoids in Inflammatory Airway Disease

摘要 该提案详细介绍了一个为期两年的计划，以准备候选人，约书亚M利维，医学博士，公共卫生硕士，职业生涯作为一个 独立的翻译研究者定位于促进我们对哮喘和过敏性气道的理解 疾病建议的调查集中在内源性大麻素作为上呼吸道炎症介质的作用。 和阿司匹林加重的呼吸道疾病（AERD）的下气道炎症。AERD在临床上 以中度至重度哮喘、鼻息肉和对阿司匹林和其他药物的类过敏反应为特征 非甾体抗炎药（NSAID）。阿司匹林挑战代表诊断的金标准 AERD，但由于专业提供者有限和对不良反应的担忧， 对程序的反应。因此，高达42%的哮喘和鼻息肉患者未能接受治疗。 AERD的准确诊断，导致以多次鼻窦手术为标志的治疗不充分，不可逆 气道重塑和美国每年超过45亿美元的医疗保健支出。候选人已经确定 AERD鼻息肉上皮中内源性2型大麻素受体表达增加， 这一发现与组织炎症无关，并有可能通过 发展创新的诊断和治疗策略。采用观察性研究设计， 细胞和生物化学方法，候选人将测试内源性大麻素 （内源性大麻素）失调与AERD的气道炎症相关，代表了一种新的 用于诊断和药物发现。这些研究将促进我们对AERD的理解， 开发生物标志物筛选小组和临床前证据，为以下试验提供支持： endocannabinoid定向疗法在这种疾病。在支持期间，候选人将利用 他在AERD的诊断和治疗方面的临床经验， 机构的AERD中心，和他的实验室技能，同时进一步发展临床研究设计的技能， 先进的生物统计学，团队领导和科学写作。这些技能将使他能够过渡到 在本奖项的第二年提交R01提案。利维医生会 合作者Andrew A.斯克里普斯健康中心（Scripps Health）的白色是AERD临床研究的全国领导者，旨在进一步 支持快速完成研究的可行性。以继续指导的形式提供的额外支持将 由大卫M. Guidot，医学博士，慢性下呼吸道疾病转化研究专家， 炎症状态。此外，利维博士还组建了一个由杰出的博士和医生组成的团队， 合作者，包括博士迈克尔H。Koval和Reneé H.摩尔，他们投入了时间， 资源，以促进这项研究的顺利完成。完成这项翻译研究将定位 候选人获得独立的NIH资金，并建立自己作为一个医生，科学家的重点是 内源性大麻素在AERD和其他形式哮喘中的临床和转化研究。

Abstract This proposal details a two-year plan to prepare the candidate, Joshua M Levy, MD, MPH, for a career as an independent translational investigator positioned to advance our understanding of asthma and allergic airway disease. The proposed investigations focus on the role of endogenous cannabinoids as mediators of upper and lower airway inflammation in Aspirin-exacerbated respiratory disease (AERD). AERD is clinically characterized by moderate to severe asthma, nasal polyps and anaphylactoid reactions to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin challenge represents the gold-standard to diagnose AERD, but is poorly utilized due to limited availability of specialized providers and concerns of adverse reactions to the procedure. Therefore, up to 42% of patients with asthma and nasal polyps fail to receive an accurate diagnosis of AERD, resulting in inadequate treatment marked by multiple sinus surgeries, irreversible airway remodeling and an annual U.S. healthcare expenditure of >$4.5 billion. The candidate has identified increased expression of the endogenous type-2 cannabinoid receptor in AERD nasal polyp epithelium, a novel finding that is independent of tissue inflammation and holds potential to advance patient care via the development of innovative diagnostic and treatment strategies. Employing an observational study design with cellular and biochemical approaches, the candidate will test the hypotheses that endogenous cannabinoid (endocannabinoid) dysregulation is associated with airway inflammation in AERD and represents a novel target for diagnosis and drug discovery. These studies will advance our understanding of AERD while developing both a biomarker screening panel and preclinical evidence lending support for the trial of endocannabinoid-directed therapeutics in this disease. During the period of support the candidate will leverage his clinical experience in the diagnosis and treatment of AERD, the regional referral patient base at his institution's AERD Center, and his laboratory skills while further developing skills in clinical study design, advanced biostatistics, team leadership, and scientific writing. These skills will enable his transition to independence with the submission of R01 proposals during the second year of this award. Dr. Levy will work collaborator Andrew A. White at Scripps Health, a national leader in the clinical study of AERD to further support the feasibility of rapid study completion. Additional support in the form of continued mentorship will be provided by David M. Guidot, MD, an expert in the translational study of lower airway disease in chronic inflammatory states. Additionally, Dr. Levy has assembled a team of extraordinary PhD and physician collaborators, including Drs. Michael H. Koval and Reneé H. Moore, who have committed their time and resources to facilitate the successful completion of this study. Completion of this translational study will position the candidate to secure independent NIH funding and establish himself as a physician-scientist with a focus on clinical and translational studies of endogenous cannabinoids in AERD and other forms of asthma.