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：
9056493
负责人：
Nirav Rati Bhakta
金额：
$ 17.16万
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/9056493
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 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 biomarker development biomarker selection burden of illness candidate marker career cytokine eosinophil eosinophilic inflammation experience high throughput technology human data human subject human tissue improved methacholine molecular phenotype mouse model neutrophil new therapeutic target novel novel strategies novel therapeutics patient oriented patient subsets performance tests periostin peripheral blood predicting response research study response screening targeted treatment treatment response

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）：这是一项申请K23 Nirav Bhakta，医学博士，博士学位，旧金山大学肺部医学博士后研究员。 Bhakta博士开始从事哮喘转化研究的年轻研究者。哮喘是肺中气道的一种慢性炎症性疾病，导致喘息，咳嗽和呼吸急促的复发发作。在过去的40年中，与哮喘相关的患病率，发病率和经济负担急剧增加。该K23奖将为Bhakta博士提供实现以下目标所需的支持：（1）发展以患者为中心的独立转化研究职业，专注于气道疾病；（2）推进将多色流式细胞术应用于人体组织样品的应用，以定量评估炎症途径；（3）在培养中使用气道上皮细胞作为解释人类数据的模型系统的专业知识；（4）将高级生物统计学方法应用于生物标志物的发展，以预测对分子靶向疗法的反应。为了实现这些目标，Bhakta博士组建了一个由主要导师组成的指导团队Prescott Woodruff博士，他是转化性哮喘研究和哮喘分子表型的专家；转化哮喘研究和气道上皮细胞生物学专家约翰·法希（John Fahy）博士；和4个赠款咨询委员会成员：马克·安塞尔（Mark Ansel）博士，马克·安塞尔（Mark Ansel）博士，具有免疫细胞子集和多色流程仪的专业知识的免疫学家；研究人员迪恩·谢泼德（Dean Sheppard）博士研究哮喘小鼠模型中的炎症途径；以及戴维·埃尔（David Erle）博士，他是研究哮喘基因网络的高通量技术和统计方法的专家；以及在高通量数据分析方面拥有丰富经验的高级生物统计学家马克·塞加尔（Mark Segal）博士。人们越来越认识到哮喘不是一种疾病，而是具有许多不同的形式，导致严重程度和对患者之间药物的反应的差异。这些差异很可能是由炎症的不同潜在途径占主导地位的驱动的，这种发现的发现将为新颖的靶向疗法的发展提供依据。通过T辅助2（Th2）细胞驱动的炎症的一种识别，导致了一种新型的血液生物标志物（骨膜素），该途径预测了对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靶向疗法的概念。但是，TH2炎症仅解释了一部分哮喘，并且有必要识别其他途径，尤其是对于严重且对标准疗法反应的10％的哮喘患者。拟议的研究将调查IL-17细胞因子驱动的一种这样的途径的作用，初步的发现导致我们假设我们的嗜酸性粒细胞炎症和严重哮喘的两种基本特征：过度的气道狭窄和粘液过度生产。正在进行的严重哮喘患者进行的支气管镜研究将被利用以获取气道洗涤和组织以检验这些假设。通过流式细胞术和显微镜检查，将评估在这些组织中IL-17细胞因子表达细胞的数量，并与炎性细胞，临床气道变窄以及确定粘液过量产生。重要的是，拟议的研究将将这些数据与对分离细胞的实验相结合，以在血液和痰液中发展出反映肺中IL-17驱动的炎症的生物标志物。这些生物标志物具有通过提供测试来确定最有可能对制药公司开发的IL-17靶向药物做出反应的人来改善哮喘护理的潜力。