Examining Mechanisms of Synergy between Asthma Exacerbations and RV Infection

检查哮喘加重和 RV 感染之间的协同机制

• 批准号: 9177968
• 负责人: Joshua Kennedy
• 金额: $ 17.55万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177968
• 关键词: Accident and Emergency department; Accounting; Adaptor Signaling Protein; Address; Advisory Committees; Agonist; Allergic; Allergic inflammation; Appointment; Arkansas; Asthma; Automobile Driving; Autopsy; Biological Markers; Biology; Carbachol; Cell Culture Techniques; Cells; Cellular biology; Child; Childhood; Clinical; Common Cold; Coughing; Development; Disease; Down-Regulation; Emergency Situation; Environment; Epithelial; Epithelial Cells; Epithelium; Evolution; Exhibits; Exposure to; Extrinsic asthma; Faculty; Figs - dietary; Foundations; Future; Generations; Genes; Goals; Hour; Human; Human Subject Research; Hypersensitivity; IgE; Immune; Immune response; Immunologist; Immunology; Individual; Infection; Inflammatory; Inflammatory Response; Institution; Interleukin-13; Interleukin-5; Interleukins; Internal Medicine; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Lung; Lymphoid; Mediating; Medical; Mentors; Mission; Monoclonal Antibodies; Nasal Lavage Fluid; Outcome; Pathway interactions; Patients; Pediatric Hospitals; Population; Prevention strategy; Production; Public Health; Publishing; Quality of Care; Research; Research Design; Research Institute; Research Personnel; Respiratory Signs and Symptoms; Rhinovirus; Risk; Role; Satellite Viruses; Science; Scientist; Severities; Severity of illness; Shortness of Breath; Slice; Small Interfering RNA; Symptoms; Syndrome; System; TLR3 gene; TSLP gene; Techniques; Time; Tissues; Training; Translating; Translational Research; Tretinoin; Universities; Viral; Virus; Virus Diseases; Wheezing; airway hyperresponsiveness; allergic response; asthmatic; asthmatic airway; career; career development; cellular targeting; clinical care; clinically relevant; cytokine; density; design; experience; immunoregulation; improved; in vivo; insight; mRNA Expression; novel; pediatric department; prevent; pyroglyphid; receptor; research study; respiratory; response; sensor; skills; viral RNA

PROJECT SUMMARY/ABSTRACT Dr. Kennedy is an Allergist/Immunologist at the University of Arkansas for Medical Sciences Departments of Pediatrics and Internal Medicine and a young investigator at Arkansas Children's Hospital Research Institute. A three-pronged mission to perform cutting-edge research, provide outstanding clinical care, and pursue educational excellence summarizes his overarching academic career objectives. His training and experience have enabled him to develop the skills and insight necessary to provide high-quality care to patients with asthma and allergic disorders, as well as providing a foundation for human subjects research. The primary objective for this mentored career development award proposal is to further Dr. Kennedy's knowledge and abilities in basic and translational investigation. This objective will specifically enable him to achieve my long-term research goals, including: 1) understanding the immune responses accounting for synergy between asthma exacerbations and infection with RV, 2) developing biomarkers of asthma disease severity and exacerbation following RV infection, and 3) translating this research into clinically relevant prevention and intervention strategies for patients with asthma. Asthma is prevalent in ~12% of the US population, and RV is recognized as the most important virus producing the common cold syndrome worldwide. Unlike patients without asthma who generally develop upper respiratory symptoms during colds, asthmatics with an RV infection may exhibit lower respiratory symptoms (e.g., cough, wheeze, shortness of breath). In fact, RV is associated with 60% to 80% of asthma exacerbations in children requiring treatment in the emergency department9-11. Despite such strong relationships, a significant knowledge gap exists with regards to the mechanisms whereby RV exacerbates asthma symptoms. Recent developments in cytokine biology have increasingly emphasized the importance of respiratory epithelial- derived cytokines in creating the milieu that promotes the evolution of allergic immune responses. The overall goal of this proposal is to understand the association between RV infection and the epithelial immune responses that bridge the allergic response to infection in asthmatics. We hypothesize that RV infection modulates epithelial cytokine expression [Interleukin (IL)-25 and thymic stromal lymphopoietin (TSLP)] in asthmatics with bias towards an allergic inflammatory response, and this underlies infection- mediated increases airway hyper-responsiveness (AHR). To address this hypothesis, we have a unique approach that brings together an in vivo study of epithelial-derived cytokines from subjects with asthma exacerbations, primary epithelial cell cultures, and a novel precision cut lung slice (PCLS) explant system allowing comparison of RV infections in asthmatic and non-asthmatic tissues. Using a cross-sectional design in a pediatric emergency department, we will compare cytokine signatures within nasal washes of asthmatics with RV-induced exacerbations and controls with cold symptoms and compare these levels with asthma symptoms. In ex vivo approaches, we will study mechanisms driving the production of IL-25 and TSLP by Toll-like receptor (TLR)-3 and Retinoic Acid Inducible Gene-I (RIG-I)-like receptors (RLR), both important in recognition of RV within epithelial cells. Finally, we will use the human airways PCLS to evaluate the effects of IL-25 and TSLP on AHR to carbachol and compare these responses between tissue derived from donors with and without asthma. By evaluating mechanisms of synergy that bridge the role of epithelial-derived cytokines to RV infection and asthma exacerbations, we will elucidate cytokine signatures and delineate pathways involved that will provide insight into the inflammatory environment produced by RV leading to exacerbations of asthma. Further, the studies within this proposal provide a firm foundation for research independence, allowing progression through further investigation of cellular targets (e.g., innate lymphoid type 2 cells (ILC2), mast cells) for these cytokines in RV-induced asthma exacerbations. To accomplish his research and academic goals, Dr. Kennedy has assembled a multi-tiered mentoring group with a wide breadth of experience. Interactions with his primary scientific co-mentors (Drs. Richard Kurten, Usha Ponnappan, and Reynold Panettieri) and his Scientific Advisory Committee (SAC) will enhance his understanding of the basic mechanisms of RV immunopathogenesis, develop research design skills, and expand his knowledge of advanced statistical techniques. Interactions with Dr. Stacie Jones, Chief of Pediatric Allergy and Immunology and primary career development mentor, will serve to improve his translational research acumen and enhance career development opportunities. Further, a Departmental Clinician Scientist Mentoring Committee composed of successful researchers at his institution has been in place since the beginning of his faculty appointment. This multi-tiered mentoring system will provide scientific and career development guidance that will enable Dr. Kennedy to become an independent researcher and an experienced clinician scientist specializing in RV-induced exacerbations of asthma.

项目概要/摘要 肯尼迪博士是阿肯色大学医学科学系的过敏症专家/免疫学家 阿肯色州儿童医院研究中心的儿科和内科教授和一名年轻研究员 研究所。三管齐下的使命是进行尖端研究、提供出色的临床护理和 追求卓越教育总结了他的总体学术生涯目标。他的训练和 经验使他能够发展必要的技能和洞察力，为患者提供高质量的护理 患有哮喘和过敏性疾病的患者，并为人类受试者研究提供基础。 这项指导性职业发展奖提案的主要目标是进一步推进肯尼迪博士的事业 基础和转化调查的知识和能力。这一目标将特别使他能够 实现我的长期研究目标，包括：1）了解免疫反应 哮喘加重和 RV 感染之间的协同作用，2) 开发哮喘生物标志物 RV 感染后疾病的严重程度和恶化，以及 3) 将这项研究转化为临床 哮喘患者的相关预防和干预策略。 哮喘在约 12% 的美国人口中流行，RV 被认为是最重要的病毒 在世界范围内产生普通感冒综合症。与没有哮喘的患者不同，他们通常会出现上呼吸道感染。 感冒期间出现呼吸道症状，RV 感染的哮喘患者可能会出现下呼吸道症状 （例如咳嗽、喘息、气短）。事实上，RV 与 60% 至 80% 的哮喘恶化有关 需要在急诊室接受治疗的儿童9-11。尽管关系如此牢固，但一个重要的 关于 RV 加剧哮喘症状的机制存在知识差距。最近的 细胞因子生物学的发展越来越强调呼吸道上皮细胞的重要性 衍生的细胞因子创造促进过敏性免疫反应进化的环境。整体 该提案的目标是了解 RV 感染与上皮免疫之间的关系 缓解哮喘患者对感染的过敏反应。我们假设 RV 感染 调节上皮细胞因子表达 [白细胞介素 (IL)-25 和胸腺基质淋巴细胞生成素 (TSLP)] 在患有过敏性炎症反应的哮喘患者中，这是感染的基础- 介导增加气道高反应性（AHR）。为了解决这个假设，我们有一个独特的 该方法汇集了来自哮喘受试者的上皮衍生细胞因子的体内研究 恶化、原代上皮细胞培养和新型精密切割肺切片 (PCLS) 外植体系统 允许比较哮喘和非哮喘组织中的 RV 感染。使用横截面设计 在儿科急诊科，我们将比较哮喘患者鼻洗液中的细胞因子特征 RV 引起的恶化和感冒症状的控制，并将这些水平与哮喘症状进行比较。 在离体方法中，我们将研究 Toll 样受体驱动 IL-25 和 TSLP 产生的机制 (TLR)-3​​ 和视黄酸诱导基因-I (RIG-I) 样受体 (RLR)，两者对于识别 RV 都很重要 上皮细胞内。最后，我们将使用人类气道PCLS来评估IL-25和TSLP的效果 比较 AHR 对卡巴胆碱的反应，并比较来自有和没有卡巴胆碱的供体的组织之间的这些反应 哮喘。通过评估桥接上皮细胞因子与 RV 作用的协同机制 感染和哮喘恶化，我们将阐明细胞因子特征并描绘相关途径 将深入了解 RV 产生的导致哮喘恶化的炎症环境。 此外，该提案中的研究为研究独立性提供了坚实的基础，允许 通过进一步研究细胞靶标（例如先天淋巴样 2 细胞 (ILC2)、肥大 细胞）在 RV 诱导的哮喘恶化中发现这些细胞因子。 为了实现他的研究和学术目标，肯尼迪博士组建了多层次的指导团队 具有广泛经验的团队。与他的主要科学合作导师（理查德博士）的互动 Kurten、Usha Ponnappan 和 Reynold Panettieri）及其科学顾问委员会 (SAC) 将加强 他了解 RV 免疫发病机制的基本机制，培养研究设计技能，以及 扩展他对先进统计技术的了解。与儿科主任 Stacie Jones 博士的互动 过敏和免疫学和主要职业发展导师，将有助于提高他的转化能力 研究敏锐度并增加职业发展机会。此外，部门临床科学家 自该机构成立以来，由其所在机构的成功研究人员组成的指导委员会就已成立 他的教职任命的开始。这种多层次的指导体系将提供科学和职业指导 发展指导将使肯尼迪博士成为一名独立的研究员和经验丰富的 专门研究 RV 引起的哮喘恶化的临床科学家。