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

摘要 博士惠特尼史蒂文斯是终身资格的助理教授在过敏和免疫学的部门在 西北大学范伯格医学院。她的临床和研究兴趣集中在阿司匹林 急性呼吸道疾病（AERD），一种由慢性鼻窦炎和慢性鼻窦炎临床三联征组成的疾病， 鼻息肉（CRSwNP）、哮喘和对环氧合酶-1酶抑制剂的敏感性。AERD是 与显著的发病率、巨大的社会经济负担和对生活质量的负面影响相关。 不幸的是，AERD发病机制的基础还没有得到很好的定义。因此，目前 受影响的患者的诊断和治疗选择仍然有限，使得AERD成为一个巨大的未满足的临床需求。 这个职业发展奖，在博士的指导下。 AERD发病机制的细胞和分子机制，以促进对这种疾病的理解 过程史蒂文斯博士有初步证据表明嗜碱性粒细胞，以及某些花生四烯酸 与阿司匹林耐受的患者相比，AERD患者鼻息肉中的代谢产物升高 CRSwNP。目前建议的中心假设是嗜碱性粒细胞和15-脂氧合酶的产物 通路促进过度的鼻窦炎性反应和严重的临床特征观察 在AERD患者中。这一假设将通过3个不重叠但互补的目标来解决：1） 嗜碱性粒细胞浸润和活化增强与AERD临床疾病严重程度的相关性; 2） AERD鼻黏膜嗜碱性粒细胞募集和激活机制的研究 息肉;和3）15-脂氧合酶产物在促进息肉中的作用的检查和表征。 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生成的最新数据来进一步调查各个领域 目前还没有很好的理解。这项工作也将导致扩大什么将成为 最大的临床验证AERD队列研究之一。重要的是，这个奖项将提供博士。 史蒂文斯与额外的职业发展和培训需要建立自己的成功的研究团队， 从导师那里独立出来，并在AERD发病机制研究方面取得了显著进展。

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.