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: 10160767
• 负责人: Kathleen Mary Buchheit
• 金额: $ 19.76万
• 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/10160767
• 关键词: Adult; Affect; Allergic Disease; Antibody Formation; Aspirin; Asthma; Automobile Driving; B-Cell Activation; Biometry; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Complement Activation; Consumption; Cytometry; Data; Data Analyses; Development; Development Plans; Diagnosis; Disease; Environment; Five-Year Plans; Functional disorder; Funding; Genetic Transcription; Goals; IL5RA gene; IgE; IgG4; Immune System Diseases; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Institution; Interleukin-5; Interleukins; Investigation; Laboratories; Lead; Leadership; Leukotriene Production; Liquid substance; Measurement; Measures; Mediator of activation protein; Medical; Mentorship; Molecular; Mucous Membrane; Nasal Polyps; Nature; Nose; Observational Study; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Preparations; Physicians; Plasma Cells; Polypectomy; Polyps; Population; Positioning Attribute; Process; Production; Productivity; Prospective Studies; Prostaglandin D2; Prostaglandin Production; Proteins; Quality of life; Reaction; Recurrence; Research Design; Research Personnel; Resources; Respiration; Respiratory System; Role; Sampling; Scientist; Secure; Severities; Signal Transduction; Sinus; Surrogate Markers; Symptoms; Techniques; Testing; Time; Tissues; Transcript; Triad Acrylic Resin; Tryptase; United States; United States National Institutes of Health; Work; Writing; aspirin-exacerbated respiratory disease; base; biobank; career; career development; chronic rhinosinusitis; cohort; cyclooxygenase 1; cysteinyl-leukotriene; deep sequencing; effective therapy; eosinophil; eosinophilic inflammation; experience; inhibitor/antagonist; insight; interleukin-5 receptor; mast cell; mepolizumab; multidimensional data; new therapeutic target; novel; patient tolerability; polyposis; prospective; research and development; respiratory; skills; transcriptome sequencing; translational scientist

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.

该建议详细介绍了为候选人凯瑟琳·M·布赫海特（Kathleen M. Buchheit）做准备的五年计划 作为一名独立翻译的研究者，其定位是为了影响我们对过敏性和 免疫疾病。拟议的调查着重于白介素（IL）-5和本地的作用 免疫球蛋白驱动呼吸道注射和肥大细胞激活的免疫球蛋白在阿司匹林效应中激活 呼吸道疾病（AERD）。 AERD的特征是哮喘，严重的慢性鼻孔炎和鼻腔炎 息肉病，白细胞三烯和前列腺素产生过多，呼吸反应 环氧酶-1抑制剂。候选人观察到AERD患者具有独特的 在转录本和蛋白质上表达高水平IL-5受体的血浆细胞群 水平。此外，她发现患有AERD的受试者患有异常的局部鼻息 免疫球蛋白的产生，与鼻息音严重程度相关，也证明了升高 与阿司匹林耐受性患者相比，鼻息肉IgE和IgG4。使用细胞和分子 技术，候选人将测试IL-5受体驱动鼻部独特子集的假设 息肉浆细胞驱动AERD呼吸道中致病性免疫球蛋白的产生， 并且可以通过用与 mepolizumab。这些研究将促进我们对AERD发病机理的理解，导致 鉴定该疾病的新型治疗靶标。在候选人的支持期间 将利用她在治疗鼻多息病和AERD，区域和地区的临床经验 她机构的Aerd Center的全国转诊患者基础以及她的实验室技能 机械临床研究设计的发展技能，高级计算生物统计学 维数据分析，团队领导和科学写作。 Buchheit博士将在 医学博士Tanya Laidlaw和医学博士Joshua Boyce的遗产，AERD和机制的专家 炎。此外，Buchheit博士还组建了一支非凡的医师科学家团队 包括Drs。 Shiv Pillai，Frances Eun-Hyung Lee，Soumya Raychaudhuri和Peter Weller 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。 他们的心态以及BWH的科学和临床环境以及翻译工作 和职业发展计划，将定位候选人，以确保独立的NIH资金和 将自己确立为身体科学家，重点是AERD和慢性的机械临床试验 鼻孔炎。