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

IL-5 和局部鼻息肉免疫球蛋白产生在阿司匹林加重的呼吸系统疾病中的作用

• 批准号: 10165118
• 负责人: Kathleen Mary Buchheit
• 金额: $ 5.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-19 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165118
• 关键词: Affect; Allergic Disease; Aspirin; Asthma; Automobile Driving; Biometry; Clinical; Clinical Research; Clinical Trials; Consumption; Data Analyses; Development Plans; Diagnosis; Disease; Environment; Five-Year Plans; Funding; Goals; IgE; IgG4; Immune System Diseases; Immunoglobulins; Impairment; Inflammation; Inflammatory; Institution; Interleukin-5; Investigation; Laboratories; Lead; Leadership; Leukotriene Production; Medical; Mentorship; Molecular; Mucous Membrane; Nasal Polyps; Nose; Pathogenesis; Pathogenicity; Patients; Physicians; Plasma Cells; Population; Positioning Attribute; Production; Prostaglandin Production; Proteins; Quality of life; Reaction; Research Design; Resources; Respiration; Respiratory System; Role; Scientist; Secure; Severities; Techniques; Testing; Time; Tissues; Transcript; Triad Acrylic Resin; United States; United States National Institutes of Health; Work; Writing; aspirin-exacerbated respiratory disease; base; career; career development; chronic rhinosinusitis; cyclooxygenase 1; cysteinyl-leukotriene; experience; inhibitor/antagonist; insight; interleukin-5 receptor; mast cell; mepolizumab; multidimensional data; new therapeutic target; patient tolerability; polyposis; research and development; respiratory; skills; translational scientist

PROJECT ABSTRACT 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.

项目摘要 这份提案详细说明了一项五年计划，为候选人凯瑟琳·M·布赫海特医学博士的职业生涯做好准备。 独立翻译研究员定位于影响我们对过敏和免疫学的理解 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的作用。 阿司匹林加重呼吸系统疾病(AERD)的呼吸道炎症和肥大细胞激活。 AERD的特征是哮喘、严重的慢性鼻窦炎并鼻息肉、半胱氨酸过量 白三烯和前列腺素的产生，以及对环氧合酶-1抑制剂的呼吸反应。这个 一位候选人观察到，AERD患者有一组独特的浆细胞，这些浆细胞高表达 IL-5受体在转录和蛋白水平的表达。此外，她还发现受试者 AERD患者局部鼻息肉免疫球蛋白产生异常，与鼻息肉相关 与阿司匹林耐受患者相比，鼻息肉IgE和IgG4也升高。 利用细胞和分子技术，候选人将检验以下假设：一个独特的IL-1子集- 5受体驱动的鼻息肉浆细胞推动呼吸道产生致病免疫球蛋白 AERD的靶向IL-5可以减轻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 确定这种疾病的新治疗靶点。在支持期间，候选人将 利用她在治疗鼻息肉和AERD方面的临床经验， 她所在机构AERD中心的转诊病人基础，以及她的实验室技能，同时她还进一步发展了技能 在机械聚焦的临床研究设计中，用于高维数据分析的计算生物统计学， 团队领导力和科学写作。Buchheit博士将在医学博士Tanya Laidlaw和 乔舒亚·博伊斯，医学博士，AERD和炎症机制的专家。此外，布赫海特博士还 组建了一支由Shiv Pillai博士、France Eun-hyung Lee博士、 Soumya Raychaudhuri和Peter Weller，他们投入了时间、资源和专业知识来促进 她的职业发展和研究目标。他们的指导以及科学和临床环境 BWH，连同翻译工作和职业发展计划，将使应聘者获得 独立资助NIH，并将自己确立为一名专注于机械性临床的内科科学家 急性呼吸窘迫综合征和慢性鼻窦炎的试验。