Endogenous Cannabinoids in Inflammatory Airway Disease

炎症性气道疾病中的内源性大麻素

• 批准号: 10532789
• 负责人: Joshua M Levy
• 金额: $ 7.83万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532789
• 关键词: Adult; Adverse reactions; Affect; Agonist; Air; Airway Disease; American; Anaphylaxis; Aspirin; Asthma; Award; Biochemical; Biological Assay; Biological Markers; Biometry; CNR2 gene; Caring; Chronic; Clinical; Clinical Research; Data; Development; Diagnosis; Diagnostic; Disease; Doctor of Philosophy; Dose; Drug Screening; Drug Targeting; Electrical Resistance; Endocannabinoids; Enzyme Inhibitor Drugs; Epithelial Cells; Epithelium; Face; Funding; Future; Genetic Transcription; Health; Health Expenditures; Human; Inflammation; Inflammatory; Ingestion; Institution; Intervention; Investigation; Laboratories; Leadership; Leukocytes; Leukotrienes; Life; Liquid substance; Logistic Regressions; Lung diseases; Mediator; Mentorship; Modeling; Nasal Epithelium; Nasal Polyps; Non-Steroidal Anti-Inflammatory Agents; Observational Study; Operative Surgical Procedures; Patient Care; Patients; Pharmaceutical Preparations; Physicians; Population; Positioning Attribute; Procedures; Prostaglandin-Endoperoxide Synthase; Provider; Reaction; Reporting; Research Design; Resources; Role; Sampling; Scientist; Screening procedure; Secure; Series; Sinus; Site; Symptoms; Syndrome; Testing; Therapeutic; Time; Tissues; United States; United States National Institutes of Health; Validation; Work; Writing; accurate diagnosis; airway inflammation; airway remodeling; allergic airway disease; aspirin-exacerbated respiratory disease; asthmatic; base; biobank; biomarker identification; biomarker panel; cannabinoid receptor; career; clinical diagnostics; clinical practice; cofactor; comorbidity; cost; cyclooxygenase 2; cytokine; design; diagnostic biomarker; diagnostic criteria; diagnostic strategy; disease diagnosis; drug discovery; emerging adult; experience; high risk; human model; improved; in vitro Model; innovation; insight; migration; new therapeutic target; novel; novel diagnostics; novel marker; participant enrollment; pre-clinical; response; screening panel; skills; small molecule; translational scientist; translational study; treatment strategy

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.

抽象的 该提案详细介绍了一项两年计划，旨在帮助候选人 Joshua M Levy（医学博士、公共卫生硕士）为职业生涯做好准备 独立转化研究者致力于增进我们对哮喘和过敏性气道的理解 拟议的研究重点是内源性大麻素作为上层介质的作用。 临床上阿司匹林加剧的呼吸道疾病（AERD）中的下呼吸道炎症。 其特征是中度至重度哮喘、鼻息肉以及对阿司匹林和其他药物的过敏反应 非甾体类抗炎药（NSAID）代表了诊断的金标准。 AERD，但由于专业提供者的可用性有限以及对不良反应的担忧而没有得到充分利用 因此，高达 42% 的哮喘和鼻息肉患者未能接受手术。 准确诊断 AERD，导致多次鼻窦手术治疗不充分，且不可逆转 候选人已确定美国每年的医疗支出超过 45 亿美元。 AERD 鼻息肉上皮内源性 2 型大麻素受体表达增加，这是一种新的 这一发现与组织炎症无关，并有可能通过以下方式促进患者护理： 采用观察性研究设计来制定创新的诊断和治疗策略。 细胞和生化方法，候选人将测试内源性大麻素的假设 （内源性大麻素）失调与 AERD 中的气道炎症有关，代表了一种新的机制。 这些研究将增进我们对 AERD 的理解。 开发生物标志物筛选小组和临床前证据，为试验提供支持 在支持期间，候选人将利用内源性大麻素导向的治疗方法。 他在 AERD 诊断和治疗方面的临床经验，他的区域转诊患者基地 机构的 AERD 中心，以及他的实验室技能，同时进一步发展临床研究设计技能， 先进的生物统计学、团队领导力和科学写作能力将使他能够过渡到。 Levy 博士将在该奖项的第二年开展独立工作并提交 R01 提案。 斯克里普斯健康中心 (Scripps Health) 的安德鲁·A·怀特 (Andrew A. White) 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。将以持续指导的形式提供额外支持。 由慢性下气道疾病转化研究专家 David M. Guidot 医学博士提供 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 Michael H. Koval 博士和 Renée H. Moore 博士，他们投入了时间和精力 促进本研究成功完成的资源 完成本转化研究将定位。 获得独立 NIH 资助并将自己定位为专注于以下领域的医师科学家的候选人 内源性大麻素治疗 AERD 和其他形式哮喘的临床和转化研究。

项目成果

Concordance of SARS-CoV-2 Results in Self-collected Nasal Swabs vs Swabs Collected by Health Care Workers in Children and Adolescents.

儿童和青少年自行采集的鼻拭子与医护人员采集的拭子中 SARS-CoV-2 结果的一致性。

• 发表时间: 2022-09-13
• 作者: Waggoner, Jesse J;Vos, Miriam B;Tyburski, Erika A;Nguyen, Phuong;Ingersoll, Jessica M;Miller, Candace;Sullivan, Julie;Griffiths, Mark;Stone, Cheryl;Benoit, Macarthur;Benedit, Laura;Seitter, Brooke;Jerris, Robert;Levy, Joshua M;Kraft, Coll
• 通讯作者: Kraft, Coll

The Effects of Endogenous Cannabinoids on the Mammalian Respiratory System: A Scoping Review of Cyclooxygenase-Dependent Pathways.

内源性大麻素对哺乳动物呼吸系统的影响：环氧合酶依赖性途径的范围审查。

• DOI: 10.1089/can.2022.0277
• 发表时间: 2023-04-19
• 期刊: Cannabis and cannabinoid research
• 作者: Anastasia Kolousek;Ezra Pak;Oliver Liu;Mia White;Prestina Smith;Fern;a Henning;a;Michael Koval;J. Levy
• 通讯作者: J. Levy