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

 描述(由申请人提供)：本提案详细说明了一项五年计划，为候选人凯瑟琳·N·卡希尔医学博士的职业生涯做准备，以影响我们对哮喘和过敏性疾病的理解。拟议的研究重点是前列腺素(PG)D2作为阿司匹林加重的呼吸系统疾病(AERD)中嗜酸性炎症的介质所起的作用。AERD的特征是哮喘、鼻息肉伴慢性嗜酸性鼻窦炎、半胱氨酰白三烯(CysLT)产生过多，以及对环氧合酶-1抑制剂的呼吸道反应导致CysLT产生激增。阿司匹林脱敏和大剂量阿司匹林治疗为许多AERD患者提供了好处，而不会改变CysLT的产生。大剂量阿司匹林的作用机制完全不清楚。候选人观察到，阿司匹林引起的呼吸反应与PGD2/PGE2(PGD2/PGE2)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周的大剂量阿司匹林治疗会抑制PGD2水平，而血液中的嗜酸性粒细胞会上升。大剂量阿司匹林治疗导致PGD2/PGE2比率被抑制，但仅在报告临床受益的受试者中。候选人将使用细胞和生化方法测试假设，即在阿司匹林诱导的反应中释放PGD2导致效应细胞从外周迁移到呼吸道，以及阿司匹林通过以剂量依赖的方式抑制AERD受试者的PGD2/PGE2比率而导致临床益处。这些研究将促进我们对AERD发病机制和阿司匹林治疗机制的理解，为PGD2导向治疗该疾病的试验提供支持。在.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AERD中心的地区和国家转诊患者基础以及她的实验室技能，同时她还将进一步发展临床研究设计、高级生物统计学、团队领导力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。卡希尔博士将在医学博士约书亚·A·博伊斯(Joshua A.Boyce)的指导下工作，博伊斯是二十烷类生物和炎症机制方面的专家，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支非凡的内科科学家团队，其中包括Tanya M.Laidlaw博士、Elliot伊斯雷尔博士、Peter F.Weller博士和Bruce D.Levy博士，他们投入了时间、资源和专业知识来促进她的职业发展和研究目标。他们的指导、BWH的科学和临床环境，以及翻译工作和职业发展计划，将使候选人获得独立的NIH资金，并将自己确立为一名内科科学家，专注于AERD和哮喘的机械性临床试验。

 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.