Translational research on the role of IL-17 cytokines in severe asthma

IL-17细胞因子在重症哮喘中作用的转化研究

基本信息

批准号：
8840644
负责人：
Nirav Rati Bhakta
金额：
$ 13.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840644
关键词：
Accounting Adrenal Cortex Hormones Adult Advisory Committees Affect Americas Animal Model Asthma Biological Assay Biological Markers Biological Models Biopsy Biostatistical Methods Blood Breathing Bronchoalveolar Lavage Bronchoscopy California Caring Cell Count Cell Culture Techniques Cell Size Cells Cellular biology Chronic Clinical Clinical Trials Color Committee Members Coughing Data Data Analyses Development Disease Doctor of Philosophy Dose Drug Targeting Economic Burden Eosinophilia Epithelial Cells Flow Cytometry Future Gene Expression Genes Goals Goblet Cells Grant Health Heterogeneity Human Immune Immunohistochemistry Immunologist In Vitro Individual Inflammation Inflammatory Interleukin-13 Interleukin-17 Interleukin-5 Lead Lung Lung diseases Measures Mediating Mentored Patient-Oriented Research Career Development Award Mentors Metaplasia MicroRNAs Microscopic Modeling Morbidity - disease rate Mucins Mucous body substance Pathologic Pathway interactions Patient Selection Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Postdoctoral Fellow Prevalence Process Public Health Pulmonology Recurrence Research Research Personnel Role Sampling San Francisco Serum Serum Proteins Severities Shortness of Breath Smooth Muscle Societies Sputum Statistical Methods Testing Therapeutic Tissue Sample Tissues Translational Research Universities Validation Wheezing Work airway hyperresponsiveness allergic airway inflammation asthmatic base burden of illness career cytokine eosinophil eosinophilic inflammation experience high throughput technology human data human subject human tissue improved methacholine molecular phenotype mouse model neutrophil novel novel strategies novel therapeutics patient oriented performance tests periostin peripheral blood research study response screening targeted treatment

项目摘要

DESCRIPTION (provided by applicant): This is an application for a K23 award for Nirav Bhakta, MD, PhD, a postdoctoral fellow in pulmonary medicine at the University of California, San Francisco. Dr. Bhakta is beginning a career as a young investigator in translational research in asthma. Asthma is a chronic inflammatory disease of the airways in the lungs that leads to recurrent episodes of wheezing, cough and shortness of breath. There has been a dramatic increase in the prevalence, morbidity, and economic burden associated with asthma over the past 40 years. This K23 award will provide Dr. Bhakta with the support necessary to accomplish the following goals: (1) to develop an independent patient-centered translational research career focused on airway diseases; (2) to advance the application of multi-color flow cytometry to human tissue samples to quantitatively evaluate inflammatory pathways; (3) develop expertise in using airway epithelial cells in culture as a model system to interpret human data; and (4) to apply advanced biostatistical methods to the development of biomarkers to predict response to molecularly-targeted therapies. To achieve these goals, Dr. Bhakta has assembled a mentoring team comprised of a primary mentor, Dr. Prescott Woodruff, an expert in translational asthma research and molecular phenotyping of asthma; a co-mentor, Dr. John Fahy, an expert in translational asthma research and airway epithelial cell biology; and 4 grant advisory committee members: Dr. Mark Ansel, an immunologist with expertise in immune cell subsets and multi-color flow-cytometry; Dr. Dean Sheppard, a senior researcher studying inflammatory pathways in mouse models of asthma; and Dr. David Erle, an expert in the application of high-throughput technologies and statistical methods to study gene networks in asthma; and Dr. Mark Segal, a senior biostatistician with extensive experience in high-throughput data analysis. There is growing recognition that asthma is not a single disease, but rather has many different forms leading to variability in severity and response to medications between patients. It is likely that these differences are driven by the predominance of distinct underlying pathways of inflammation, the discovery of which would inform the development of novel targeted therapies. Identification of one such pathway, inflammation driven by T helper 2 (Th2) cells, has led to a novel blood biomarker (periostin) which predicts response to Th2-targeted therapy, proving the concept that molecular phenotyping can guide cytokine-targeted therapies. However, Th2 inflammation explains only a subset of asthma, and there is a need to identify other pathways, especially for the 10% of asthmatics who are severe and do not respond to standard therapies. The proposed research will investigate the role of one such pathway, inflammation driven by IL-17 cytokines, which preliminary findings lead us to hypothesize is associated with heightened eosinophilic inflammation and two cardinal features of severe asthma: excessive airway narrowing and mucous overproduction. An ongoing bronchoscopy study in severe asthmatics will be leveraged to obtain airway washings and tissues to test these hypotheses. The numbers of IL-17 cytokine- expressing cells will be assessed in these tissues with flow cytometry and microscopic examination, and their association with inflammatory cells, clinical airway narrowing, and mucous overproduction determined. Importantly, the proposed study will combine this data with experiments on isolated cells to develop biomarkers in the blood and sputum that reflect IL-17-driven inflammation in the lung. These biomarkers have the potential to improve asthma care by providing a test to identify the individuals most likely to respond to IL-17-targeted drugs already in development by pharmaceutical companies.

描述（由申请人提供）：这是 Nirav Bhakta 博士的 K23 奖项申请，他是旧金山加利福尼亚大学肺医学博士后研究员。 Bhakta 博士作为一名年轻的研究者开始了哮喘转化研究的职业生涯。哮喘是一种肺部气道的慢性炎症性疾病，会导致反复发作的喘息、咳嗽和呼吸急促。过去 40 年来，与哮喘相关的患病率、发病率和经济负担急剧增加。该 K23 奖项将为 Bhakta 博士提供实现以下目标所需的支持：（1）发展以患者为中心、专注于气道疾病的独立转化研究事业；（2）推进多色流式细胞术在人体组织样本中的应用，定量评估炎症通路； (3) 发展使用培养的气道上皮细胞作为模型系统来解释人类数据的专业知识； (4) 应用先进的生物统计学方法来开发生物标志物，以预测对分子靶向治疗的反应。为了实现这些目标，Bhakta 博士组建了一个指导团队，其中包括主要导师 Prescott Woodruff 博士，他是哮喘转化研究和哮喘分子表型分析方面的专家；共同导师 John Fahy 博士，转化哮喘研究和气道上皮细胞生物学专家； 4 名资助顾问委员会成员：Mark Ansel 博士，一位在免疫细胞亚群和多色流式细胞术方面具有专业知识的免疫学家； Dean Sheppard 博士，高级研究员，研究哮喘小鼠模型的炎症通路； David Erle 博士是应用高通量技术和统计方法研究哮喘基因网络的专家； Mark Segal 博士是一位高级生物统计学家，在高通量数据分析方面拥有丰富的经验。人们越来越认识到哮喘不是一种单一的疾病，而是有许多不同的形式，导致患者之间的严重程度和对药物的反应存在差异。这些差异很可能是由不同的炎症潜在途径的主导地位驱动的，这一点的发现将为新型靶向治疗的开发提供信息。对此类途径（由辅助性 T 2 (Th2) 细胞驱动的炎症）的鉴定，产生了一种新型血液生物标志物（骨膜蛋白），可预测对 Th2 靶向治疗的反应，证明了分子表型可以指导细胞因子靶向治疗的概念。然而，Th2 炎症只能解释哮喘的一部分，并且需要确定其他途径，特别是对于 10% 的严重哮喘患者且对标准治疗没有反应。拟议的研究将调查这样一种途径的作用，即由 IL-17 细胞因子驱动的炎症，初步研究结果使我们推测与嗜酸性粒细胞炎症加剧和严重哮喘的两个主要特征有关：气道过度狭窄和粘液分泌过多。一项正在进行的针对严重哮喘患者的支气管镜检查研究将用于获取气道冲洗液和组织来检验这些假设。将通过流式细胞术和显微镜检查评估这些组织中IL-17细胞因子表达细胞的数量，并确定它们与炎症细胞、临床气道狭窄和粘液过度产生的关系。重要的是，拟议的研究将把这些数据与分离细胞的实验结合起来，以开发血液和痰液中反映 IL-17 驱动的肺部炎症的生物标志物。这些生物标志物有潜力通过提供测试来识别最有可能对制药公司正在开发的 IL-17 靶向药物产生反应的个体来改善哮喘护理。