Endogenous Cannabinoids in Inflammatory Airway Disease

炎症性气道疾病中的内源性大麻素

• 批准号: 10378990
• 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/10378990
• 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; Epithelial Cells; Face; Funding; Future; Genetic Transcription; Gold; Health; Health Expenditures; Human; Inflammation; Inflammatory; Ingestion; Institution; Intervention; Investigation; Laboratories; Leadership; Leukocytes; Leukotrienes; Life; Liquid substance; Logistic Regressions; Lung diseases; Mediator of activation protein; 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 panel; cannabinoid receptor; career; clinical diagnostics; clinical practice; cofactor; comorbidity; cost; cyclooxygenase 2; cytokine; design; diagnostic biomarker; diagnostic criteria; diagnostic strategy; disease diagnosis; disease diagnostic; 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.

摘要