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

描述(申请人提供)：这是Nirav Bhakta，医学博士，博士，加州大学旧金山分校的博士后研究员，K23奖项的申请书。Bhakta博士作为一名年轻的哮喘转化研究研究员，开始了他的职业生涯。哮喘是一种慢性肺部呼吸道炎症性疾病，会导致反复发作的喘息、咳嗽和呼吸短促。在过去的40年里，与哮喘相关的患病率、发病率和经济负担急剧增加。这一K23奖项将为Bhakta博士提供必要的支持，以实现以下目标：(1)发展以患者为中心的独立的、专注于呼吸道疾病的转化研究事业；(2)推动多色流式细胞术在人体组织样本中的应用，以定量评估炎症途径；(3)发展将培养的呼吸道上皮细胞用作解释人类数据的模型系统的专业知识；以及(4)应用先进的生物统计学方法开发生物标记物，以预测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，成员包括主要导师Prescott Woodruff博士，转化性哮喘研究和哮喘分子表型专家；共同导师John Fahy博士，转化性哮喘研究和呼吸道上皮细胞生物学专家；以及4名赠款咨询委员会成员：擅长免疫细胞亚群和多色流式细胞术的免疫学家Mark Ansel博士，研究哮喘小鼠模型炎症途径的高级研究员Dean Seppard博士，以及应用高通量技术和统计方法研究哮喘基因网络的专家David Erle博士；马克·西格尔博士，一位在高通量数据分析方面拥有丰富经验的高级生物统计师。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，导致不同患者的严重程度和对药物的反应不同。这些差异很可能是由不同的潜在炎症途径的优势推动的，这些途径的发现将为新的靶向治疗的发展提供信息。其中一种途径，即由T辅助细胞(Th2)细胞驱动的炎症，已经导致了一种新的血液生物标记物(Periostin)，它可以预测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炎症只解释了哮喘的一小部分，有必要确定其他途径，特别是对于10%的严重且对标准治疗无效的哮喘患者。这项拟议的研究将调查其中一个途径的作用，即由IL-17细胞因子驱动的炎症，初步发现使我们假设与嗜酸性粒细胞炎症加剧和严重哮喘的两个基本特征有关：过度的气道狭窄和粘液过度产生。一项正在进行的对重症哮喘患者的支气管镜检查研究将被用来获得呼吸道冲洗液和组织来验证这些假设。用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、临床呼吸道狭窄和粘液过度生产的关系。重要的是，这项拟议的研究将把这些数据与对分离细胞的实验相结合，以开发血液和痰中反映IL-17驱动的肺部炎症的生物标记物。这些生物标记物通过提供一种测试来识别最有可能对制药公司已经在开发的IL-17靶向药物做出反应的个体，从而有可能改善哮喘的治疗。

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.