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The Role of Prostaglandin D2 in the Respiratory Symptoms of Aspirin Exacerbated Respiratory Disease

前列腺素 D2 在阿司匹林加重呼吸道疾病的呼吸道症状中的作用

基本信息

批准号：
9486819
负责人：
Katherine N Cahill
金额：
$ 9.49万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9486819
关键词：
Acute Adult Affect Allergic Disease Aspirin Asthma Award Biochemical Biology Biometry Bronchodilator Agents Cells Chemotactic Factors Chronic Chronic Sinusitis Clinical Clinical Research Clinical Trials Data Development Plans Diagnosis Dinoprostone Disease Dose Effector Cell Eicosanoids Environment Eosinophilia Epithelial Cells Exhalation Exhibits Five-Year Plans Funding Generations Goals Ibuprofen Inflammation Ingestion Institution Investigation Israel Laboratories Leadership Leukotriene E4 Leukotriene Production Life Measures Mediating Mediator of activation protein Medicine Mentors Mentorship Nasal Lavage Fluid Nasal Polyps Nose Operative Surgical Procedures PTGS2 gene Pathogenesis Patients Peripheral Pharmaceutical Preparations Physicians Population Positioning Attribute Production Prostaglandin D2 Prostaglandins Pulmonary Function Test/Forced Expiratory Volume 1 Quality of life Reaction Recurrence Reporting Research Design Research Personnel Resources Respiratory Signs and Symptoms Respiratory System Role Scientist Secure Signal Transduction Sinus Sinusitis Steroids Symptoms Testing Therapeutic Time Tissues United States United States National Institutes of Health Work Writing aspirin-exacerbated respiratory disease asthmatic patient base career career development cell motility cyclooxygenase 1 cysteinyl-leukotriene desensitization disorder control eosinophil eosinophilic inflammation experience falls improved individual variation inhibitor/antagonist insight macrophage mast cell peripheral blood polyposis public health relevance recruit research and development respiratory skills translational scientist urinary

项目摘要

DESCRIPTION (provided by applicant): This proposal details a five-year plan to prepare the candidate, Katherine N. Cahill, MD, for a career as an independent translational investigator positioned to impact our understanding of asthma and allergic disease. The proposed investigations focus on the role of prostaglandin (PG)D2 as a mediator of eosinophilic inflammation in aspirin exacerbated respiratory disease (AERD) . AERD is characterized by asthma, nasal polyposis with chronic eosinophilic sinusitis, excessive cysteinyl leukotriene (cysLT) production, and respiratory reactions to cyclooxygenase-1 inhibitors resulting in a surge in cysLT generation. Aspirin desensitization and high-dose aspirin therapy provide benefit for many patients with AERD without altering cysLT production. The mechanism of action of high-dose aspirin is entirely unknown. The candidate has observed that aspirin-induced respiratory reactions correlate with a rise in the PGD2 to PGE2 (PGD2/PGE2) ratio over basal levels and a fall in peripheral blood eosinophils. Additionally, she has discovered that 8-weeks of high-dose aspirin therapy suppress PGD2 levels while blood eosinophils rise. High-dose aspirin therapy leads to a suppressed PGD2/PGE2 ratio, but only in subjects who report clinical benefit. Employing cellular and biochemical approaches, the candidate will test the hypotheses that PGD2 release during the aspirin-induced reaction results in effector cell migration from the periphery to the respiratory tract and that aspirin leads to clinical benefit by suppressing the PGD2/PGE2 ratio in a dose- dependent manner in subjects with AERD. These studies will advance our understanding of the pathogenesis of AERD and the therapeutic mechanism of aspirin therapy lending support for the trial of PGD2-directed therapeutics in this disease. During the period of support the candidate will leverage her clinical experience in the diagnosis and treatment of AERD, the regional and national referral patient base at her institution's AERD Center, and her laboratory skills while she further develops skills in clinical study design, advanced biostatistics, team leadership, and scientific writing. These skills will enable her to transition to independence during the fourth and fifth years of the award. Dr. Cahill will work under the mentorship of Joshua A. Boyce, MD, an expert in eicosanoid biology and mechanisms of inflammation, who has an excellent record of mentoring young investigators for successful careers in academic medicine. Additionally, Dr. Cahill has assembled a team of extraordinary physician scientists, including Drs. Tanya M. Laidlaw, Elliot Israel, Peter F. Weller and Bruce D. Levy, who have committed their time, resources, and expertise to facilitate her career development and research goals. Their mentorship and the scientific and clinical environment at BWH, along with the translational work and career development plan, will position the candidate to secure independent NIH funding and to establish herself as a physician-scientist with a focus on mechanistic clinical trials in AERD and asthma.