Endogenous Cannabinoids in Inflammatory Airway Disease

摘要 这项提案详细说明了一项为期两年的计划，为候选人约书亚·M·利维，医学博士，公共卫生硕士，为他的职业生涯做准备。 独立翻译研究员定位于促进我们对哮喘和过敏性呼吸道的了解 疾病。拟议的调查重点是内源性大麻素作为上丘脑损伤的中介物的作用。 阿司匹林加重的呼吸道疾病(AERD)患者的呼吸道炎症程度较低。急性呼吸窘迫综合征在临床上 以中到重度哮喘、鼻息肉和对阿司匹林和其他药物过敏反应为特征 非甾体抗炎药。阿司匹林挑战是诊断的黄金标准 AERD，但由于专业提供者的有限可获得性以及对不利因素的担忧，利用率较低 对手术的反应。因此，高达42%的哮喘和鼻息肉患者无法接受 准确诊断AERD，导致治疗不当，以多次鼻窦手术为标志，不可逆转 气道重塑和美国每年45亿美元的医疗支出。候选人已经确定了 内源性大麻素2型受体在AERD鼻息肉上皮细胞中的表达增加 这一发现独立于组织炎症，并有可能通过 制定创新的诊断和治疗战略。采用观察性研究设计， 细胞和生化方法，候选人将检验内源性大麻素的假说 (内源性大麻素)调节失调与AERD的呼吸道炎症相关，并代表了一种新的 诊断和药物发现的目标。这些研究将促进我们对AERD的理解，同时 建立生物标记物筛选小组和临床前证据，为临床试验提供支持 内源性大麻素在此疾病中的指导治疗。在支持期间，候选人将利用 他在HIS地区转诊病人群AERD诊断和治疗方面的临床经验 和他的实验室技能，同时进一步发展临床研究设计的技能， 高级生物统计学、团队领导力和科学写作。这些技能将使他能够过渡到 在本奖项的第二年提交R01提案的独立性。利维博士将会工作 斯克里普斯健康公司的合作者安德鲁·A·怀特是AERD临床研究的全国领先者，以进一步 支持快速完成研究的可行性。以持续指导的形式提供的额外支持将是 由David M.Guidot医学博士提供，他是慢性呼吸道疾病下呼吸道疾病的翻译研究专家 炎症状态。此外，利维博士还组建了一支由杰出的博士和医生组成的团队 合作者，包括迈克尔·H·科瓦尔博士和雷内·H·摩尔博士，他们投入了时间和 协助顺利完成这项研究的资源。完成这项翻译研究将使 这位候选人希望获得独立的NIH资金，并确立自己作为内科科学家的地位，专注于 内源性大麻素在AERD和其他形式哮喘中的临床和翻译研究。

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.