Pathobiologic Transcriptional Signatures of Pulmonary Complications in Pediatric Hematopoietic Cellular Transplantation

小儿造血细胞移植肺部并发症的病理生物学转录特征

• 批准号: 10569543
• 负责人: Matthew Scott Zinter
• 金额: $ 19.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569543
• 关键词: Academic Medical Centers; Admission activity; Australia; Bioinformatics; Biological; Biological Assay; Biology; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; California; Canada; Characteristics; Child; Childhood; Childhood Injury; Classification; Clinical; Clinical Sciences; Coagulation Process; Complex; Computational Science; Critical Care; Data; Data Set; Dedications; Detection; Development; Development Plans; Diagnostic; Diagnostic tests; Disease; Endothelium; Faculty; Failure; Fibrinolysis; Fluid overload; Future; Gene Expression; Gene Expression Profile; Geography; Goals; Hematological Disease; Human; Immune; Immunologic Deficiency Syndromes; Infection; Inflammation; Injury; Interstitial Pneumonia; Intervention; Investigation; Investigational Therapies; Knowledge; Life; Lung; Lung Transplantation; Lung diseases; Lung infections; Malignant - descriptor; Measures; Mediating; Medicine; Mentors; Metagenomics; Methodology; Microbe; Modeling; Molecular; Molecular Target; Netherlands; Non-Malignant; Organism; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pediatric Hospitals; Pediatric Intensive Care Units; Pediatric cohort; Phenotype; Physicians; Population; Positioning Attribute; Pulmonary Inflammation; RNA; Research; Respiratory Tract Infections; Role; San Francisco; Scientist; Technology; Testing; Toxic effect; Training; Transcript; Translational Research; Transplant Recipients; Transplantation; Transplantation and Immune System; Treatment-related toxicity; United States; Universities; Viral; Work; accurate diagnosis; biobank; cancer therapy; career; career development; chemotherapy; clinical diagnostics; clinical practice; cohort; disease phenotype; dysbiosis; epithelial injury; experience; graft vs host disease; hematopoietic cell transplantation; high risk; improved; improved outcome; lung injury; lung microbiome; lung pathogen; metagenomic sequencing; microbial; microbial composition; microbiome; microbiome research; microbiome signature; molecular targeted therapies; mortality; next generation sequencing; pathogen; prognostic; respiratory; targeted treatment; trait; translational potential; transplant model

Project Summary/Abstract Over 2,500 children undergo hematopoietic cell transplantation (HCT) in the United States each year for an increasingly broad set of malignant and non-malignant diseases. Unfortunately, pulmonary complications after HCT are a leading cause of transplant-related mortality (TRM) and are frequently associated with a complex overlap of respiratory infection, viral reactivation, alloreactive inflammation, treatment-related lung injury, fluid overload, and other toxicities. In clinical practice, differentiation of pulmonary infection and non-infectious inflammation is challenging and failure to accurately diagnose pulmonary complications is associated with significant mortality. Further, an incomplete understanding of the varied biology of post-HCT pulmonary complications has to date limited the application of targeted therapeutics necessary to improve survival. Therefore, the goal of this K23 proposal is to advance our understanding of the pathobiology of post-HCT pulmonary complications in children. To do this, we will apply metagenomic sequencing technology to lower respiratory biospecimens from two geographically distinct pediatric cohorts. In Specific Aim 1a, we will determine the composition of the pulmonary microbiome in pediatric HCT patients with different subtypes of lung disease and will identify occult pathogens that can be implicated in disease. In Specific Aim 1b, we will model the outcome of transplant-related mortality (TRM) according to microbiomic characteristics while controlling for potentially confounding clinical traits. In Specific Aim 2a, we will analyze patterns of pulmonary gene expression in order to improve our understanding of dysregulated biological pathways involved in lung injury after HCT. In Specific Aim 2b, we will associate TRM with human gene expression signatures in order to identify high-risk patients with shared biology that may benefit from molecularly targeted interventions. In sum, these aims will develop a platform with which to more accurately diagnose pulmonary infections and identify discrete cellular pathways involved in infectious and non-infectious post-HCT lung injury. The knowledge gained from this investigation will be directly useful in improving diagnostic and prognostic classification schema necessary to adapt targeted therapeutics and improve patient outcomes. The candidate's career goal is to improve molecular characterization and treatment of pathobiologic subtypes of lung injury in children who have undergone HCT. In this K23 application, the candidate has proposed a detailed career development plan focused on developing a technical, methodological, and bioinformatics expertise in the execution of impactful research in this rapidly evolving cross-disciplinary field. The candidate is trained in Pediatric Critical Care Medicine, holds a faculty position at the University of California, San Francisco, and is well supported by an experience mentoring and scientific advising team. This K23 proposal will generate robust data to inform a subsequent R01 submission facilitating the candidate's transition to an independent scientific career aimed at improving outcomes for pediatric HCT patients with lung injury.

项目摘要/摘要 每年，超过2500名儿童接受造血细胞移植（HCT） 日益广泛的恶性和非恶性疾病。不幸的是，肺部并发症之后 HCT是移植相关死亡率（TRM）的主要原因，并且经常与复合物有关 呼吸道感染，病毒再活化，同种反应性炎症，与治疗相关的肺部损伤的重叠 超负荷和其他毒性。在临床实践中，肺部感染和非感染的分化 炎症具有挑战性，无法准确诊断肺并发症与 重大死亡率。此外，对HCT肺后肺的不同生物学的不完全理解 迄今为止，并发症限制了提高生存所必需的目标治疗剂的应用。 因此，该K23提案的目的是提高我们对HCT后病理生物学的理解 儿童的肺并发症。为此，我们将应用宏基因组测序技术来降低 来自两个地理上不同儿科同伴的呼吸生物测量。在特定的目标1a中，我们将确定 肺HCT患者的肺微生物组的组成不同的肺部疾病亚型 并将确定可能与疾病有关的神秘病原体。在特定的目标1B中，我们将建模 根据微生物特征的同时，与移植相关死亡率（TRM）的结果在控制的同时 可能会混淆临床特征。在特定的目标2a中，我们将分析肺基因表达的模式 为了提高我们对HCT后肺损伤涉及的生物学途径失调的理解。在 特定的目标2B，我们将将TRM与人类基因表达特征相关联，以识别高风险 具有共同生物学的患者可能受益于分子靶向干预措施。总而言之，这些目标将 开发一个平台，可以更准确地诊断肺部感染并识别离散的细胞 涉及传染性和非感染后HCT肺损伤的途径。从中获得的知识 调查将直接用于改善所需的诊断和预后分类模式 适应有针对性的治疗剂并改善患者预后。 候选人的职业目标是改善病原体亚型的分子表征和治疗 患有HCT的儿童的肺损伤。在此K23应用程序中，候选人提出了详细的 职业发展计划的重点是开发技术，方法论和生物信息学专业知识 在这个快速发展的跨学科领域中执行有影响力的研究。候选人接受了培训 小儿重症监护医学，在加利福尼亚大学旧金山担任教职员工，是 得到经验指导和科学咨询团队的良好支持。这个K23提案将产生强大的 数据以告知随后的R01提交，以促进候选人向独立科学的过渡 旨在改善肺损伤儿科HCT患者的结果。