The inflammatory role of the platelet in aspirin-exacerbated respiratory disease.

血小板在阿司匹林加剧的呼吸道疾病中的炎症作用。

• 批准号: 8703167
• 负责人: Tanya Maria Laidlaw
• 金额: $ 13.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703167
• 关键词: Adherence; Adhesions; Adult; Affect; Agonist; Area; Aspirin; Asthma; Award; Biochemical; Biological Assay; Biology; Biometry; Blood; Blood Platelets; Bronchoconstriction; Bronchoconstrictor Agents; Characteristics; Chronic; Clinical; Clinical Research; Commit; Complement; Data; Defect; Development Plans; Diagnosis; Dinoprostone; Disease; Dose; EP4 receptor; Eicosanoids; Environment; Eosinophilia; Five-Year Plans; Frequencies; Funding; Generations; Goals; Homeostasis; Hypersensitivity; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Ingestion; Investigation; Israel; Knowledge; Laboratories; Lead; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Leukocytes; Leukotriene A4; Leukotriene C4; Leukotriene E4; Leukotrienes; Life; Link; Lung; Lung diseases; Measures; Medicine; Mentors; Mentorship; Molecular; Nasal Polyps; Nose; P-Selectin; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Plant Roots; Platelet Activation; Population; Positioning Attribute; Production; Prostaglandins; Proteins; Reaction; Receptor Signaling; Recurrence; Relative (related person); Research Design; Research Personnel; Resources; Role; Scientist; Secure; Severities; Signal Transduction; Signaling Protein; Sinus; Sinusitis; Source; Syndrome; Testing; Thromboxane A2; Time; Tissues; Triad Acrylic Resin; United States; United States National Institutes of Health; Up-Regulation; Urine; Work; Writing; base; career; career development; cyclooxygenase 1; cyclooxygenase 2; cysteinyl-leukotriene; didactic education; eosinophil; experience; granulocyte; human WFDC2 protein; in vivo; inhibitor/antagonist; insight; leukocyte activation; leukotriene-C4 synthase; migration; monocyte; neglect; neutrophil; novel; peripheral blood; polyposis; prevent; prostaglandin EP2 receptor; public health relevance; receptor; research and development; respiratory; response; skills; urinary

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.

描述（由申请人提供）：该提案详细介绍了一个五年计划，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。这些研究集中在血小板作为阿司匹林加重的呼吸道疾病（AERD）效应物的先前未被认识的作用。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合酶-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酰白三烯生成升高相关，后者可能反映前列腺素E2产生或其受体（EP受体）功能紊乱。候选人发现，AERD患者的血小板显示出两种前列腺素E2受体EP 2和EP 4的功能降低，这降低了血小板活化的阈值，并增加了血小板对炎症粒细胞和单核细胞的粘附。结果，AERD患者的血液中含有的血小板-白细胞聚集体比阿司匹林耐受对照组的血液中的血小板-白细胞聚集体多得多。使用细胞，生物化学和分子方法的组合，候选人将测试的假设，即血小板上的异常EP 2和EP 4信号统一的现象，白三烯过度生产，组织嗜酸性粒细胞增多症，阿司匹林诱导的反应与AERD患者。这些研究结果将进一步加深我们对AERD发病机制的认识。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，以培养临床研究设计，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和第四年过渡到独立。 Laidlaw博士将在医学博士约书亚博伊斯的指导下工作，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。莱德劳博士还组建了一个由杰出的医学科学家组成的团队，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，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。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，并将自己定位为专注于AERD的医生科学家，这是一个相对被忽视的调查领域。