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

这项提案详细说明了一个五年计划，以准备候选人，凯瑟琳M。Buchelman，MD，职业生涯 作为一个独立的翻译研究者，定位于影响我们对过敏和 免疫性疾病拟议的研究重点是白细胞介素（IL）-5和局部免疫的作用 免疫球蛋白驱动呼吸道炎症和肥大细胞活化 呼吸系统疾病（AERD）。AERD的特征是哮喘、严重慢性鼻窦炎伴鼻 息肉病，过量的半胱氨酰白三烯和前列腺素的产生，以及对 环氧合酶-1抑制剂。候选人观察到AERD患者具有独特的 在转录物和蛋白质上表达高水平IL-5受体的浆细胞群 程度.此外，她发现AERD患者有异常的局部鼻息肉， 免疫球蛋白的产生，与鼻息肉的严重程度相关， 鼻息肉IgE和IgG 4与阿司匹林耐受患者相比。利用细胞和分子 技术，候选人将测试的假设，一个独特的子集IL-5受体驱动的鼻 息肉浆细胞驱动AERD中呼吸道中致病性免疫球蛋白的产生， 并且致病性免疫球蛋白的产生可以通过用 美泊利单抗这些研究将促进我们对AERD发病机制的理解， 确定这种疾病的新治疗靶点。在支持期间，候选人 将利用她在鼻息肉病和AERD治疗方面的临床经验， 在她所在机构的AERD中心的国家转诊患者基地，以及她的实验室技能，而她进一步 培养以机械为中心的临床研究设计技能，高水平的计算生物统计学， 维度数据分析、团队领导和科学写作。布赫特博士将在 Tanya Laidlaw，MD和约书亚博伊斯，MD，AERD和AERD机制专家的指导 炎症此外，布赫博士还组建了一个由杰出的医学科学家组成的团队， 包括Shiv Pillai博士、Frances Eun-Hyung Lee博士、Soumya Raychaudhuri博士和Peter Weller博士， 致力于他们的时间，资源和专业知识，以促进她的职业发展和研究目标。 他们的指导以及BWH的科学和临床环境，沿着翻译工作 和职业发展计划，将定位候选人，以确保独立的NIH资金， 确立了自己作为一个医生，科学家，重点是在AERD和慢性机械临床试验 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.