The inflammatory role of the platelet in 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，旨在为候选人Tanya Laidlaw医学博士提供成为过敏和免疫学领域的独立研究员的知识和专业知识。这些研究的重点是血小板作为阿司匹林加重的呼吸系统疾病(AERD)的效应者之前未被认识到的作用。AERD的特征是哮喘、复发性鼻息肉和因摄入阿司匹林或其他环氧合酶-1抑制剂而发生的呼吸反应。虽然病因不明，但该综合征始终与组织嗜酸性粒细胞增多和半胱氨酰白三烯的生成增加有关，后者可能反映前列腺素E2的产生或其受体(EP受体)的功能障碍。这位候选人发现，AERD患者的血小板显示出两种前列腺素E2受体EP2和EP4的功能下降，这降低了他们血小板激活的门槛，并允许血小板与炎性粒细胞和单核细胞粘附性增加。结果，与阿司匹林耐受对照组相比，AERD患者的血液中含有更多的血小板-白细胞聚集物。使用细胞、生化和分子方法的组合，候选人将检验这一假设，即血小板上异常的EP2和EP4信号统一了AERD患者的白三烯过度生产、组织嗜酸性粒细胞增多和阿司匹林诱导的反应的现象。这些研究结果将促进我们对AERD发病机制的理解。在支持期间，候选人将通过教学课程补充她的实验室技能，以发展临床研究设计、高级生物统计学和科学写作方面的技能。这将有助于她在获奖的第三年和第四年过渡到独立。莱德洛博士将在医学博士约书亚·博伊斯的指导下工作，博伊斯是二十烷类生物和炎症机制方面的专家，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。莱德洛博士还组建了一支杰出的内科科学家团队，其中包括埃利奥特·伊斯雷尔博士、玛丽安娜·卡斯特尔斯博士和K·弗兰克·奥斯汀博士，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。在他们的指导和指导下，在BWH理想的科学和临床环境中，翻译工作、教学课程和职业发展计划将使候选人能够获得独立的NIH资金，并确立自己作为内科科学家的地位，专注于AERD，这是一个相对被忽视的研究领域。

DESCRIPTION (provided by applicant): This proposal details a five-year plan to provide the candidate, Tanya Laidlaw, MD, with the knowledge and expertise to become an independent investigator in the field of Allergy and Immunology. The studies focus on a previously unrecognized role for platelets as effectors of aspirin-exacerbated respiratory disease (AERD). AERD is characterized by asthma, recurrent nasal polyps, and respiratory reactions that occur upon ingestion of aspirin or other inhibitors of cyclooxygenase-1. Although the cause is unknown, the syndrome is consistently associated with tissue eosinophilia and elevated generation of cysteinyl leukotrienes, the latter of which may reflect a disturbance in the production of prostaglandin E2 or the function of its receptors (EP receptors). The candidate has discovered that platelets from individuals with AERD demonstrate decreased function of two prostaglandin E2 receptors, EP2 and EP4, which lowers the threshold for activation of their platelets and allows for increased platelet adhesion onto inflammatory granulocytes and monocytes. As a result, the blood of individuals with AERD contains substantially more platelet-leukocyte aggregates than does the blood of aspirin tolerant controls. Using a combination of cellular, biochemical, and molecular approaches, the candidate will test the hypothesis that abnormal EP2 and EP4 signaling on platelets unifies the phenomena of leukotriene overproduction, tissue eosinophilia, and aspirin-induced reactions in patients with AERD. The results from these studies will advance our understanding of the pathogenesis of AERD. During the period of support the candidate will complement her laboratory skills with didactic coursework to develop skills in clinical study design, advanced biostatistics, and scientific writing. This will then facilitate her transition to independence during the third and fourth yearsof the award. Dr. Laidlaw will work under the mentorship of Joshua 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. Dr. Laidlaw has also assembled a team of extraordinary physician scientists, including Drs. Elliot Israel, Mariana Castells, and K. Frank Austen, who have committed their time, resources, and expertise to facilitate her career development and research goals. Under their mentorship and guidance, in an ideal scientific and clinical environment at the BWH, the translational work, didactic curriculum, 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 AERD, a relatively neglected area of investigation.