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

• 批准号: 9284384
• 负责人: Katherine N Cahill
• 金额: $ 19.76万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284384
• 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; Individual; 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; Recruitment Activity; Recurrence; Reporting; Research Design; Research Personnel; Resources; Respiratory Signs and Symptoms; Respiratory System; Respiratory tract structure; Role; Scientist; Secure; Signal Transduction; Sinus; Sinusitis; Steroids; Symptoms; Testing; Therapeutic; Time; Tissues; United States; United States National Institutes of Health; Variant; 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; inhibitor/antagonist; insight; macrophage; mast cell; peripheral blood; polyposis; public health relevance; research and development; respiratory; skills; translational scientist; urinary

 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.

 描述（由申请人提供）：该提案详细说明了一个五年计划，以准备候选人，凯瑟琳N。卡希尔，医学博士，职业生涯作为一个独立的翻译调查定位，以影响我们对哮喘和过敏性疾病的理解。拟议的调查集中在前列腺素（PG）D2作为阿司匹林加重呼吸道疾病（AERD）中嗜酸性粒细胞炎症介质的作用。AERD的特征为哮喘、鼻息肉病伴慢性嗜酸性鼻窦炎、过量半胱氨酰白三烯（cysLT）生成以及对环氧合酶-1抑制剂的呼吸反应，导致cysLT生成激增。阿司匹林脱敏和高剂量阿司匹林治疗为许多AERD患者提供了益处，而不改变cysLT的产生。大剂量阿司匹林的作用机制完全未知。该候选人观察到阿司匹林诱导的呼吸反应与PGD 2/PGE 2（PGD 2/PGE 2）比值高于基础水平和外周血嗜酸性粒细胞下降相关。此外，她还发现，8周的高剂量阿司匹林治疗抑制了PGD 2水平，同时血液嗜酸性粒细胞上升。高剂量阿司匹林治疗导致PGD 2/PGE 2比值降低，但仅在报告临床获益的受试者中。采用细胞和生物化学方法，候选人将检验以下假设：阿司匹林诱导反应期间的PGD 2释放导致效应细胞从外周迁移至呼吸道，阿司匹林通过以剂量依赖性方式抑制AERD受试者中的PGD 2/PGE 2比值而产生临床获益。这些研究将进一步加深我们对AERD发病机制的理解，并为研究PGD 2靶向治疗AERD提供支持。期间 在支持期间，候选人将利用她在AERD诊断和治疗方面的临床经验，她所在机构的AERD中心的区域和国家转诊患者基础，以及她的实验室技能，同时她进一步发展临床研究设计，高级生物统计学，团队领导和科学写作方面的技能。这些技能将使她能够在获奖的第四年和第五年过渡到独立。卡希尔博士将在约书亚A.医学博士博伊斯是类花生酸生物学和炎症机制方面的专家，他在指导年轻研究人员在学术医学领域取得成功方面有着出色的记录。此外，卡希尔博士还组建了一个由杰出的医生科学家组成的团队，其中包括坦尼娅·M·放大图片作者：Peter F. Weller和布鲁斯D.利维，谁承诺他们的时间，资源和专业知识，以促进她的职业发展和研究目标。他们的指导和BWH的科学和临床环境，沿着翻译工作和职业发展计划，将使候选人能够获得独立的NIH资金，并将自己定位为一名医生-科学家，专注于AERD和哮喘的机械临床试验。