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个五年计划，为候选人Tanya Laidlaw， MD提供知识和专业知识，成为过敏和免疫学领域的独立研究者。这些研究的重点是血小板作为阿司匹林加重呼吸系统疾病（AERD）的效应器的先前未被认识到的作用。AERD的特征是哮喘、复发性鼻息肉和摄入阿司匹林或其他环氧化酶-1抑制剂后发生的呼吸反应。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酸白三烯生成升高有关，后者可能反映前列腺素E2生成或其受体（EP受体）功能紊乱。候选人发现，来自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，这降低了其血小板激活的阈值，并允许血小板增加对炎症粒细胞和单核细胞的粘附。因此，与阿司匹林耐受对照者相比，患有AERD的个体血液中含有更多的血小板-白细胞聚集物。该候选人将结合细胞、生化和分子方法，检验血小板上异常的EP2和EP4信号传导是否与AERD患者白三烯过量产生、组织嗜酸性粒细胞增多和阿司匹林诱导的反应有关。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来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。这将有助于她在获得该奖项的第三和第四年过渡到独立。Laidlaw博士将在Joshua Boyce医学博士的指导下工作，Joshua Boyce是类二十烷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。莱德劳博士还组建了一个由杰出的内科科学家组成的团队。Elliot Israel， Mariana Castells和K. Frank Austen，他们投入了他们的时间，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获得独立的NIH资助，并使自己成为一名专注于AERD的内科科学家，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.