Pediatric Sepsis Biorepository and Clinical Database

儿科脓毒症生物储存库和临床数据库

基本信息

批准号：
10608134
负责人：
Frances B Balamuth
金额：
$ 22.96万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-11 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10608134
关键词：
Accident and Emergency department Adult Age Apoptosis Applied Research Bioenergetics Biological Biological Assay Biological Specimen database Biology Blood Plasma Volume Blood specimen Cessation of life Characteristics Child Clinical Clinical Data Clinical Research Complex Critical Care Critical Illness Data Data Collection Data Science Development Diagnosis Disease Electronic Health Record Emergency Care Emergency Medicine Enrollment Evaluation Flow Cytometry Functional disorder Funding Future Glean Goals Hour Hypoxemia Individual Infection Inflammatory Life Link Liquid substance Lymphocyte Activation Lymphocyte Function Medical Metabolic Morbidity - disease rate Multiple Organ Failure Organ Outcome Patients Pattern Pharmaceutical Preparations Phase Phenotype Pilot Projects Plasma Process Production Proteomics Quality-Adjusted Life Years Registries Research Research Infrastructure Research Personnel Resuscitation Risk Sampling Sepsis Shock Site Specimen Surface Techniques Testing Thrombocytopenia Time biomarker panel clinical database clinical phenotype cohort comorbidity cytokine data pipeline data registry design exhaustion experience feasibility testing high dimensionality high risk individual variation innovation lymphocyte proliferation metabolomics mortality multidisciplinary new therapeutic target novel strategies participant enrollment pathogen pediatric emergency pediatric sepsis phenotypic data precision medicine prospective response sample collection targeted treatment translational immunology

项目摘要

PROJECT SUMMARY Sepsis is broadly defined as life-threatening organ dysfunction caused by infection. However, the experience of sepsis varies widely between individuals and within individuals. Such inter- and intra-individual heterogeneity reflects complex, evolving pathobiology induced by host-pathogen interactions and modified by pre-existing patient characteristics and ongoing medical treatments. It is highly unlikely that a single—or even a small panel—of biomarkers will characterize an individual’s pathobiology with enough accuracy to unlock precision medicine approaches in sepsis. The challenge, therefore, is to identify and accurately characterize relevant phenotypes of sepsis and develop enrichment strategies to design and test novel targeted therapies. For this project, we propose testing the feasibility of novel approaches to collect, process, and analyze biologic data representing the immuno-inflammatory-metabolic response to infection early in the sepsis course and link this information to relevant organ dysfunction-based phenotype data from the electronic health record (EHR). We have assembled a multi-disciplinary team composed of experts in translational immunology, pediatric emergency medicine, critical care, and data science. We will test the feasibility of collecting and processing blood samples of different volumes for deep phenotyping at the pre-resuscitation phase, which is a critical timepoint, as well as 48 hours later to capture dynamic changes post-resuscitation. We will use these samples to characterize the functional immuno-inflammatory-metabolic biology using high dimensional flow cytometry to track surface and intracellular markers of lymphocyte proliferation, apoptosis, exhaustion, and cytokine production. In addition, we will extend flow cytometric techniques to perform bioenergetic evaluation, and will perform proteomic evaluation of the plasma immuno-inflammatory-metabolomic response using O-link. This project will take advantage of extensive clinical research infrastructure at the three study sites. In addition, the investigators will have access to innovative biologic assays at CHOP which will allow our collaborative team to glean key biologic phenotypes from critically ill and complex patients. In the R21 phase, we will complete a single-center pilot study to test the feasibility of collecting, processing, and analyzing the optimal blood specimens for deep phenotyping in the early phase of sepsis, linking them to the EHR registry data, and developing and testing a data pipeline to characterize the patients’ organ dysfunction-based clinical phenotypes. In the R33 phase, we will expand the sample collection to three sites and perform a proof-of- concept analysis to determine if there are differences in the immuno-inflammatory-metabolomic patterns of the children who develop either of the high-risk organ dysfunction-based sepsis phenotypes. Identifying relevant biological patterns in the R33 phase can then lead to future hypothesis-driven mechanistic studies and the development of targeted therapies.

项目摘要败血症广泛地定义为威胁生命的器官功能障碍，由感染引起。但是，败血症在个体和个体内部差异很大。这种间和个体异质性反映由宿主 - 病原体相互作用引起的复杂，不断发展的病理生物学，并通过预先存在的修改患者特征和正在进行的医疗治疗。一个单人甚至很小的不可能面板 - 生物标志物将以足够准确的精度来表征个人的病理生物学败血症的医学方法。因此，挑战是识别并准确表征相关的败血症和开发富集策略的表型设计和测试新型靶向疗法。为了这项目，我们建议测试新型方法收集，处理和分析生物学数据的可行性代表败血症初期感染的免疫炎症代谢反应，并将其联系起来来自电子健康记录（EHR）的基于相关器官功能障碍的表型数据的信息。我们组建了一个由转化免疫学专家组成的多学科团队急诊医学，重症监护和数据科学。我们将测试收集和处理的可行性在震动阶段进行深层表型的不同体积的血液样本，这是一个关键时间点以及48小时后，以捕获令人震惊的动态变化。我们将使用这些样品用高维流式细胞仪到淋巴细胞增殖，凋亡，疲劳和细胞因子的轨道表面和细胞内标记生产。此外，我们将扩展流式细胞仪技术以进行生物能评估，并将使用O-link对血浆免疫炎症 - 炎性 - 代谢响应进行蛋白质组学评估。该项目将利用三个研究地点的广泛临床研究基础设施。在此外，调查人员将可以在Chop上获得创新的生物测定法，这将使我们合作团队，从重病和复杂的患者那里收集关键的生物学表型。在R21阶段，我们将完成一项单中心试点研究，以测试收集，处理和分析的可行性在败血症的早期阶段进行深层表型的最佳血液标本，将其链接到EHR注册表数据，并开发和测试数据管道，以表征患者的基于器官功能障碍的临床表型。在R33阶段，我们将将样本收集扩展到三个站点，并执行证明概念分析以确定免疫炎症 - 代谢模式是否存在差异发展基于高风险器官功能障碍的败血症表型的儿童。确定相关性然后，R33阶段中的生物学模式可以导致未来的假设驱动的机械研究和靶向疗法的开发。