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。

基本信息

批准号：
8528709
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
项目类别：
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/8528709
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

项目摘要

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）：该提案详细介绍了为候选人Tanya Laidlaw，医学博士提供的五年计划，并提供了成为过敏和免疫学领域的独立研究者的知识和专业知识。这些研究集中在血小板作为阿司匹林诊断呼吸道疾病（AERD）的作用方面的作用。 AERD的特征是哮喘，复发性鼻息肉以及摄入阿司匹林或其他环氧酶-1抑制剂后发生的呼吸反应。尽管原因尚不清楚，但该综合征一直与组织嗜酸性粒细胞和白细胞三烯的产生升高有关，后者可能反映了前列腺素E2或其受体功能的干扰（EP受体）。该候选人发现，来自AERD个体的血小板表明，两个前列腺素E2受体EP2和EP4的功能降低，这降低了其血小板的阈值，并允许增加血小板上对炎症性颗粒细胞和单核细胞的粘附增加。结果，与阿司匹林耐受对照的血液相比，AERD个体的血液含有大得多的血小板 - 白细胞骨料。使用细胞，生化和分子方法的结合，候选者将测试血小板上异常EP2和EP4信号的假设，可以统一白细胞过量产生，组织嗜酸性粒细胞嗜酸性粒细胞和阿司匹林诱导的AERD患者反应的现象。这些研究的结果将提高我们对AERD发病机理的理解。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。然后，这将促进她在该奖项的第三年和第四年过渡到独立性。 Laidlaw博士将在eicosanoid生物学和炎症机制的专家Joshua Boyce的指导下工作，后者在指导年轻研究人员的学术医学职业方面有着良好的记录。 Laidlaw博士还召集了包括Drs在内的非凡医师科学家团队。以色列，玛丽安娜·卡斯特尔（Mariana Castells）和K. Frank Austen致力于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的理想科学和临床环境中，翻译工作，教学课程和职业发展计划将使候选人确保获得独立的NIH资助，并确立自己的医生科学家，重点关注AERD，这是一个相对忽视的研究领域。