Cellular and Molecular Mechanisms of the Pathogenesis of Aspirin Exacerbated Respiratory Disease

摘要 惠特尼·史蒂文斯博士是华盛顿大学过敏和免疫学系符合终身教职条件的助理教授。 西北大学范伯格医学院。她的临床和研究兴趣主要集中在阿司匹林 急性呼吸系统疾病(AERD)，一种由慢性鼻-鼻窦炎和 鼻息肉(CRSwNP)、哮喘和对环氧合酶-1酶抑制剂的敏感性。AERD是 与严重的发病率、巨大的社会经济负担和对生活质量的负面影响有关。 不幸的是，AERD发病的潜在机制还不是很清楚。因此，当前 对受影响患者的诊断和治疗选择仍然有限，使AERD成为一个巨大的未得到满足的临床需求。 这个职业发展奖，在罗伯特·施莱默博士的指导下，专注于调查 AERD发病的细胞和分子机制有助于提高对该病的认识 进程。史蒂文斯博士有初步证据表明，嗜碱性细胞以及某些花生四烯酸 与阿司匹林耐受患者相比，AERD患者鼻息肉中代谢产物升高 CRSWNP。当前提议的中心假设是嗜碱性细胞和15-脂氧合酶的产物 途径促进鼻窦炎症反应的夸大和严重的临床特征观察 在AERD患者中。这一假设将由三个互不重叠但互补的目标来解决：1) 急性呼吸窘迫综合征嗜碱性粒细胞浸润和激活增强与临床病情严重程度的关系 嗜碱性粒细胞在AERD鼻腔内募集和激活机制的鉴定 以及3)检测和表征15-脂氧合酶产物在促进息肉生长中的作用。 在AERD鼻息肉中观察到慢性炎症。 这项研究的创新之处在于，它将使用史蒂文斯博士最近产生的新数据来进一步研究领域 目前还不太清楚的AERD。这项工作还将导致将成为 可供研究的最大的经临床验证的AERD队列之一。重要的是，这一奖项将为Dr。 史蒂文斯需要额外的职业发展和培训来建立自己的成功研究团队， 从她的导师那里建立独立，并极大地推进了她研究AERD发病机制的事业。

ABSTRACT Dr. Whitney Stevens is a tenure-eligible Assistant Professor within the Division of Allergy and Immunology at the Northwestern University Feinberg School of Medicine. Her clinical and research interests focus on Aspirin Exacerbated Respiratory Disease (AERD), a disease consisting of the clinical triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma and sensitivity to inhibitors of the cyclooxygenase-1 enzyme. AERD is associated with significant morbidity, large socioeconomic burden, and negative impact on quality of life. Unfortunately, the underlying mechanisms of AERD pathogenesis are not well defined. As a result, current diagnostic and treatment options for affected patients remain limited, making AERD a large unmet clinical need. This career development award, under the mentorship of Dr. Robert Schleimer, focuses on investigating the cellular and molecular mechanisms of AERD pathogenesis to advance the understanding of this disease process. Dr. Stevens has preliminary evidence suggesting that basophils, as well as certain arachidonic acid metabolites, are elevated in nasal polyps of patients with AERD compared to patients with aspirin tolerant CRSwNP. The central hypothesis of the current proposal is that basophils and products of the 15-lipoxygenase pathway promote the exaggerated sinonasal inflammatory response and severe clinical characteristics observed in patients with AERD. This hypothesis will be addressed by 3 non-overlapping but complementary aims: 1) Correlation of the enhanced infiltration and activation of basophils with clinical disease severity in AERD; 2) Identification of the mechanisms responsible for the recruitment and activation of basophils in AERD nasal polyps; and 3) Examination and characterization of the effects of 15-lipoxygenase products in promoting the chronic inflammation observed in AERD nasal polyps. This study is innovative in that it will use novel recent data generated by Dr. Stevens to further investigate areas of AERD that are not currently well understood. This work will also lead to the expansion of what will become one of the largest clinically validated AERD cohorts available for study. Importantly, this award will provide Dr. Stevens with additional career development and training needed to build her own successful research team, establish independence from her mentor and significantly advance her career studying AERD pathogenesis.