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.

项目摘要/摘要 肯尼迪博士是阿肯色大学医学科学系的过敏症师/免疫学家 阿肯色州儿童医院研究的儿科和内科医学和年轻研究者 研究所。执行尖端研究，提供出色的临床护理和 追求卓越的教育总结了他的总体学术职业目标。他的训练和 经验使他能够发展提供高质量护理所必需的技能和见解 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。 该指导职业发展奖提案的主要目标是进一步肯尼迪博士 基本和翻译调查中的知识和能力。这个目标将特别使他能够 实现我的长期研究目标，包括：1）了解有关的免疫反应 哮喘加剧与感染RV之间的协同作用，2）发展哮喘的生物标志物 RV感染后疾病的严重程度和加剧，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％的美国人群中普遍存在，RV被认为是最重要的病毒 在世界范围内产生普通的冷综合症。与没有哮喘的患者通常发展上层 感冒期间呼吸道症状，感染RV感染的哮喘患者可能表现出下呼吸道症状 （例如，咳嗽，喘息，呼吸急促）。实际上，RV与60％至80％的哮喘患者有关 在需要治疗的儿童中9-11。尽管有如此牢固的关系，但很重要 关于RV加剧哮喘症状的机制，知识差距存在。最近的 细胞因子生物学的发展越来越强调呼吸性上皮的重要性 衍生的细胞因子在创建促进过敏性免疫反应演变的环境中。总体 该提议的目标是了解RV感染与上皮免疫之间的关联 弥合哮喘感染过敏反应的反应。我们假设RV感染 调节上皮细胞因子表达[白介素（IL）-25和胸腺基质淋巴细胞生成素（TSLP）] 在对过敏性炎症反应有偏见的哮喘患者中，这是感染的基础 介导的增加气道高反应性（AHR）。为了解决这一假设，我们有一个独特的 方法汇集了哮喘受试者上皮细胞因子的体内研究 恶化，原发性上皮细胞培养和一种新颖的精确切割肺切片（PCLS）外植体系统 允许比较哮喘和非心血管组织中的RV感染。在 一个儿科急诊室，我们将比较哮喘患者鼻洗的细胞因子特征 RV引起的患有冷症状的恶化和对照将这些水平与哮喘症状进行比较。 在离体方法中，我们将研究通过Toll样受体推动IL-25和TSLP产生的机制 （TLR）-3和视黄酸诱导型基因-I（RIG-I）样受体（RLR），都在识别RV的情况下很重要 在上皮细胞内。最后，我们将使用人类气道PCL来评估IL-25和TSLP的影响 在AHR到Carbachol上，并比较了来自有或没有的供体的组织之间的这些反应 哮喘。通过评估协同的机制，弥合上皮细胞因子对RV的作用 感染和哮喘恶化，我们将阐明涉及的细胞因子特征和描述途径 将提供有关RV产生的炎症环境导致哮喘加剧的洞察力。 此外，该提案中的研究为研究独立性提供了坚定的基础，允许 通过进一步研究细胞靶标（例如，先天淋巴2型细胞（ILC2），桅杆的进展 细胞）这些细胞因子在RV诱导的哮喘加重中。 为了实现他的研究和学术目标，肯尼迪博士聚集了多层指导 小组具有广泛的经验。与他的主要科学领域的互动（理查德博士 Kurten，Usha Ponnappan和Reynold Panettieri及其科学咨询委员会（SAC）将增强 他对RV免疫病发生，发展研究设计技能的基本机制的理解和 扩大他对先进统计技术的了解。与儿科主任Stacie Jones博士的互动 过敏和免疫学以及主要职业发展导师将有助于改善他的翻译 研究敏锐度并增强职业发展机会。此外，部门临床医生 自从他的机构中，由成功的研究人员组成的指导委员会自从 他任教的开始。这个多层指导系统将提供科学和职业 开发指导将使肯尼迪博士成为一名独立研究人员和经验丰富的 临床医生专门研究RV引起的哮喘加重。