Novel Markers of Treatment Responsiveness for Pediatric Acute Asthma Exacerbations

小儿哮喘急性加重治疗反应性的新标志物

• 批准号: 10548194
• 负责人: Nidhya Navanandan
• 金额: $ 18.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548194
• 关键词: Acceleration; Accident and Emergency department; Accounting; Acute; Acute Respiratory Distress Syndrome; Address; Adrenal Cortex Hormones; Airway Resistance; Asthma; Automobile Driving; Biological; Biological Markers; Biological Response Modifier Therapy; Bronchodilator Agents; Caring; Child; Childhood; Childhood Asthma; Chronic; Clinical; Clinical Research; Development Plans; Effectiveness; Emergency Care; Emergency Medicine; Emergency department visit; Enrollment; Ensure; Epithelial Cells; Funding; Future; Genes; Goals; Home; Hospitalization; Individual; Infrastructure; Inhalation; Institution; Interferons; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leadership; Length of Stay; Measures; Mentors; Mentorship; Methods; Modeling; Molecular Genetics; Morbidity - disease rate; Nasal Epithelium; Nose; Oscillometry; Outcome; Outpatients; Physicians; Physiological; Positioning Attribute; Prediction of Response to Therapy; Predictive Analytics; Prospective Studies; Research; Research Methodology; Resources; Scientist; Spirometry; Testing; Therapeutic Intervention; Time; Training; Translational Research; Validation; Variant; Work; asthma exacerbation; career; career development; clinical practice; clinical predictive model; clinical predictors; diagnostic biomarker; experience; feasibility trial; hospital readmission; improved; improved outcome; individualized medicine; innovation; mortality; multidisciplinary; novel; novel diagnostics; novel marker; pediatric emergency; personalized approach; predictive modeling; prospective; pulmonary function; response; skills; success; targeted treatment; therapy development; tool; transcriptome; transcriptome sequencing; transcriptomics; treatment response; treatment strategy; unnecessary treatment

PROJECT SUMMARY Acute asthma exacerbations are the primary cause of morbidity and mortality in children with asthma. Current treatment for acute asthma exacerbations in the pediatric Emergency Department (ED) follows an one- size-fits all approach including inhaled bronchodilators and systemic corticosteroids. However, treatment response to initial protocolized therapies is variable and unpredictable presenting a significant management challenge for ED clinicians. Unfortunately, the pathobiologic mechanisms driving treatment response remain unclear, and an effective method to predict treatment response does not exist. Thus, ED clinicians frequently struggle with treatment and disposition decisions leading to over-utilization of therapies, prolonged ED length of stay, and hospitalizations in responders, and delays in appropriate therapy for non-responders. The extensive variation and inefficiency in care highlights the critical need for tools to inform more precise and effective ED management strategies for acute asthma exacerbations. The nasal transcriptome and airway oscillometry (AOS) are novel biologic and physiologic markers with strong potential to address this unmet knowledge and practice gap. This proposal aims to apply an innovative biomarker-directed, individualized approach to ED asthma management by leveraging these novel markers to pursue the following specific aims: 1) determine the utility of AOS as an objective measure of ED treatment responsiveness; 2) identify airway endotypes of ED treatment responsiveness using nasal transcriptomics, and 3) derive and internally validate a clinical prediction rule incorporating biologic and physiologic markers to determine ED treatment responsiveness in children with acute asthma exacerbations. To achieve these aims, the candidate, Nidhya Navanandan, MD, will leverage an existing study infrastructure for enrolling children with acute asthma exacerbations in the ED, developed in conjunction with her mentors during her institutional career development award. As a pediatric emergency medicine physician, Dr. Navanandan is uniquely positioned to accomplish the proposed K23 research and training aims. Her long-term goal is to become an expert in clinical and translational research methods to improve the effectiveness of emergency care for pediatric asthma. Dr. Navanandan has developed a detailed career development plan consisting of mentorship, didactic coursework, and hands-on laboratory and research conduct experience in order to expand her knowledge and skills in leadership of prospective studies, discovery and application of novel markers for clinical practice, and predictive analytics. Dr. Navanandan has assembled a multidisciplinary team of mentors with extensive clinical and translational research experience and topical expertise in the above realms to ensure her success in achieving the stated specific aims and career goals. This proposal will allow Dr. Navanandan to transition to an independent physician-scientist and prepare her for future R01-funding.

项目概要 哮喘急性加重是哮喘儿童发病和死亡的主要原因。 目前儿科急诊科（ED）对哮喘急性发作的治疗遵循以下一种方法： 尺寸适合所有方法，包括吸入支气管扩张剂和全身性皮质类固醇。然而，治疗 对初始方案治疗的反应是可变且不可预测的，因此需要进行重要的管理 急诊科临床医生面临的挑战。不幸的是，驱动治疗反应的病理生物学机制仍然存在 尚不清楚，并且不存在预测治疗反应的有效方法。因此，急诊科临床医生经常 与治疗和处置决策作斗争，导致治疗过度使用、急诊时间延长 有反应者的住院时间和住院时间，以及无反应者的适当治疗的延迟。这 护理方面的广泛差异和低效率凸显了对工具的迫切需要，以提供更准确和更准确的信息 针对哮喘急性发作的有效 ED 管理策略。鼻转录组和气道 示波法（AOS）是新型生物和生理标志物，具有解决这一未满足问题的巨大潜力 知识与实践的差距。该提案旨在应用一种创新的生物标志物导向的、个性化的 通过利用这些新标志物来实现 ED 哮喘管理方法，以实现以下具体目标： 1) 确定 AOS 作为 ED 治疗反应性客观衡量标准的效用； 2) 识别气道 使用鼻转录组学确定 ED 治疗反应的内型，以及 3) 推导并内部验证 结合生物和生理标志物来确定 ED 治疗的临床预测规则 哮喘急性发作儿童的反应能力。为了实现这些目标，候选人 Nidhya 医学博士纳瓦南丹将利用现有的研究基础设施来招募患有急性哮喘的儿童 急诊部病情恶化，是在她机构职业发展期间与她的导师共同开发的 奖。作为一名儿科急诊医学医师，纳瓦南丹博士拥有独特的优势来完成以下任务： 提出了K23研究和培训目标。她的长期目标是成为临床和医学领域的专家。 提高小儿哮喘紧急护理有效性的转化研究方法。博士。 纳瓦南丹制定了详细的职业发展计划，包括指导、教学课程、 以及实践实验室和研究进行经验，以扩展她的知识和技能 领导前瞻性研究、临床实践新标志物的发现和应用，以及 预测分析。 Navanandan 博士组建了一支多学科导师团队，拥有广泛的临床经验 以及上述领域的转化研究经验和主题专业知识，以确保她在 实现既定的具体目标和职业目标。该提案将使纳瓦南丹博士能够过渡到 独立医师科学家，并为她未来的 R01 资助做好准备。