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

描述（由申请人提供）：这是一个K23奖的Nirav Bhakta，医学博士，博士，博士后研究员在肺部医学在加州大学弗朗西斯科分校。Bhakta博士作为一名年轻的哮喘转化研究调查员开始了自己的职业生涯。哮喘是肺部气道的慢性炎症性疾病，导致反复发作的喘息、咳嗽和呼吸急促。在过去的40年里，哮喘的患病率、发病率和经济负担急剧增加。该K23奖项将为Bhakta博士提供必要的支持，以实现以下目标：（1）发展以患者为中心的独立转化研究事业，重点关注气道疾病;（2）推进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）发展使用培养的气道上皮细胞作为解释人类数据的模型系统的专业知识;以及（4）将先进的生物统计学方法应用于生物标志物的开发，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，由主要导师Prescott Woodruff博士（转化型哮喘研究和哮喘分子表型专家）、共同导师John Fahy博士（转化型哮喘研究和气道上皮细胞生物学专家）和4名赠款咨询委员会成员组成：Mark Ansel博士，免疫学家，擅长免疫细胞亚群和多色流式细胞术; Dean Sheppard博士，研究哮喘小鼠模型炎症通路的高级研究员;大卫尔勒博士，高通量技术和统计方法在哮喘基因网络研究中的应用专家;马克西格尔博士，在高通量数据分析方面具有丰富经验的高级生物统计学家。越来越多的人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炎症的不同潜在途径的优势驱动的，其发现将为新型靶向治疗的开发提供信息。一种这样的途径，由辅助性T细胞2（Th 2）驱动的炎症的鉴定，导致了一种新的血液生物标志物（骨膜蛋白），它预测对Th 2靶向治疗的反应，证明了分子表型可以指导靶向治疗的概念。然而，Th 2炎症仅解释了哮喘的一个子集，需要确定其他途径，特别是对于10%严重且对标准治疗无反应的哮喘患者。拟议的研究将调查一个这样的途径，由IL-17细胞因子驱动的炎症的作用，初步研究结果使我们假设与嗜酸性粒细胞炎症和严重哮喘的两个主要特征有关：过度气道狭窄和粘液过度产生。一项正在进行的严重哮喘患者支气管镜检查研究将被用来获得气道冲洗液和组织来检验这些假设。将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，并确定其与炎性细胞、临床气道狭窄和粘液过度产生的相关性。重要的是，拟议的研究将联合收割机将这些数据与分离细胞的实验相结合，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。这些生物标志物有可能通过提供一种测试来识别最有可能对制药公司已经开发的IL-17靶向药物产生反应的个体，从而改善哮喘护理。

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.