The Role of IL-5 and Local Nasal Polyp Immunoglobulin Production in Aspirin-Exacerbated Respiratory Disease

这份提案详细说明了一项为候选人凯瑟琳·M·布赫海特的职业生涯做准备的五年计划 作为一名独立的翻译调查员，定位于影响我们对过敏和 免疫性疾病。拟议的调查重点是白细胞介素5和局部 免疫球蛋白驱动阿司匹林加重的呼吸道炎症和肥大细胞激活 呼吸道疾病(AERD)。AERD的特征是哮喘、严重的慢性鼻-鼻窦炎和鼻腔 息肉病，过多的半胱氨基白三烯和前列腺素产生，以及呼吸道反应 环氧合酶-1抑制剂。这位候选人观察到，AERD患者有一种独特的 在转录本和蛋白上均高水平表达IL-5受体的浆细胞群 级别。此外，她还发现患有AERD的受试者有异常的局部鼻息肉。 免疫球蛋白的产生，这与鼻息肉的严重程度相关，也显示出升高 鼻息肉IgE和IgG4与阿司匹林耐受患者的比较。使用细胞和分子 技术，候选人将测试假设一个独特的子集的IL-5受体驱动的鼻腔 息肉浆细胞驱动AERD患者呼吸道产生致病免疫球蛋白， 通过靶向IL-5可以减少致病免疫球蛋白的产生 甲波利珠单抗。这些研究将促进我们对AERD发病机制的理解，从而导致 这种疾病新的治疗靶点的确定。在对候选人的支持期间 将利用她在治疗鼻息肉和AERD方面的临床经验，区域和 在她的机构AERD中心的全国转诊患者基础上，以及她的实验室技能，同时她进一步 培养以机械为重点的临床研究设计、计算生物统计学方面的技能 维度数据分析、团队领导和科学写作。布赫海特博士将在 指导医学博士Tanya Laidlaw和医学博士Joshua Boyce，AERD和机制方面的专家 发炎。此外，布赫海特博士还组建了一支由杰出的内科科学家组成的团队 包括Shiv Pillai博士、France Eun-hyung Lee博士、Soumya Raychaudhuri博士和Peter Weller博士 投入他们的时间、资源和专业知识来促进她的职业发展和研究目标。 他们的指导和BWH的科学和临床环境，以及翻译工作 和职业发展计划，将使候选人获得独立的NIH资金并 确立自己作为内科科学家的地位，专注于AERD和慢性病的机械性临床试验 鼻窦炎。

This proposal details a five-year plan to prepare the candidate, Kathleen M. Buchheit, MD, for a career as an independent translational investigator positioned to impact our understanding of allergic and immunologic disease. The proposed investigations focus on the role of interleukin (IL)-5 and local immunoglobulins driving respiratory tract inflammation and mast cell activation in aspirin-exacerbated respiratory disease (AERD). AERD is characterized by asthma, severe chronic rhinosinusitis with nasal polyposis, excessive cysteinyl leukotriene and prostaglandin production, and respiratory reactions to cyclooxygenase-1 inhibitors. The candidate has observed that patients with AERD have a unique population of plasma cells that express high levels of IL-5 receptor at both the transcript and protein levels. Additionally, she has discovered that subjects with AERD have aberrant local nasal polyp immunoglobulin production, which correlates with nasal polyp severity, and also demonstrate elevated nasal polyp IgE and IgG4 as compared to aspirin-tolerant patients. Employing cellular and molecular techniques, the candidate will test the hypotheses that a unique subset of IL-5 receptor-driven nasal polyp plasma cells drives production of pathogenic immunoglobulins in the respiratory tract in AERD, and that the pathogenic immunoglobulin production can be mitigated by targeting IL-5 with mepolizumab. These studies will advance our understanding of the pathogenesis of AERD leading to the identification of novel therapeutic targets for this disease. During the period of support the candidate will leverage her clinical experience in the treatment of nasal polyposis and AERD, the regional and national referral patient base at her institution’s AERD center, and her laboratory skills while she further develops skills in mechanistically-focused clinical study design, computational biostatistics for high- dimensional data analysis, team leadership, and scientific writing. Dr. Buchheit will work under the mentorship of Tanya Laidlaw, MD and Joshua Boyce, MD, experts in AERD and mechanisms of inflammation. Additionally, Dr. Buchheit has assembled a team of extraordinary physician-scientists including Drs. Shiv Pillai, Frances Eun-Hyung Lee, Soumya Raychaudhuri, and Peter Weller, who have committed their time, resources, and expertise to facilitate her career development and research goals. Their mentorship and the scientific and clinical environment at BWH, along with the translational work 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 mechanistic clinical trials in AERD and chronic rhinosinusitis.