Establishment of a multi-center biobank of patient-specific induced pluripotent stem cells for pediatric sepsis research

建立用于儿童脓毒症研究的患者特异性诱导多能干细胞多中心生物库

• 批准号: 10649014
• 负责人: Mihir R Atreya
• 金额: $ 21.57万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-04 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649014
• 关键词: Acceleration; Acute; Address; Antibiotics; Benchmarking; Bioinformatics; Biological Markers; Biology; CD34 gene; Caring; Cell Line; Cell Therapy; Cells; Child; Clinical Data; Clinical Trials; Collecting Cell; Collection; Communities; Complex; Core Facility; Coupled; Critically ill children; Cryopreservation; Databases; Dedications; Development; Disease; Disease model; Drug Screening; Endothelial Cells; Enrollment; Exposure to; Faculty; Failure; Funding; Generations; Genomics; Goals; Health; Heterogeneity; Human; Immune response; Individual; Infection; Infrastructure; Institution; Leadership; Leukocytes; Life; Malignant Childhood Neoplasm; Modeling; Molecular Target; National Institute of General Medical Sciences; Organ; Organoids; Outcome; PTPRC gene; Pathogenesis; Pathway interactions; Patient Recruitments; Patients; Pediatric cohort; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phased Innovation Awards; Phenotype; Pluripotent Stem Cells; Precision therapeutics; Process; Protocols documentation; RNA; Research; Research Personnel; Risk; Role; Sampling; Scientific Advances and Accomplishments; Scientific Inquiry; Sepsis; Septic Shock; Serum; Source; Standardization; Therapeutic; Whole Blood; XCL1 gene; advanced disease; age related; biobank; biological heterogeneity; body system; cell type; differentiation protocol; disease phenotype; epigenomics; experience; experimental study; gene environment interaction; genome editing; improved; improved outcome; in vitro Model; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; monocyte; mortality risk; multiple omics; next generation; novel; participant enrollment; patient response; pediatric patients; pediatric sepsis; pluripotency; precision medicine; prevent; response; risk stratification; scale up; septic; transcriptomics

Establishment of a multi-center biobank of patient-specific pluripotent stem cells for pediatric sepsis research. PROJECT SUMMARY: Sepsis is the final common pathway among those with serious infections and kills more children than cancer in the U.S each year. Yet, there are no therapies available for pediatric sepsis beyond early antibiotics and organ support. Multiple levels of heterogeneity at the patient, organ, and cellular levels have significantly impeded scientific progress. Although precision medicine approaches have been used to sift through patient- level differences, we fundamentally lack a comprehensive understanding of how heterogeneous cellular responses contribute to sepsis pathogenesis. Thus, there is a crucial need for human sepsis biorepositories to unravel cell-specific mechanistic pathways and accelerate the development of novel sepsis therapeutics. We seek to bridge this gap by developing an unprecedented biobank of patient-specific induced pluripotent stem cells (iPSCs) derived from children with sepsis. Human iPSCs can be used as a renewable and expandable source of any cell type and have been used for precision modeling of numerous disease states. However, it remains unknown whether they can serve as robust in vitro models of sepsis – an acute condition with complex gene-environment interactions and driven primarily by the host response. Through this phased innovation award, we seek to establish the ability of patient-specific iPSC derived cells to capture disease phenotypes and recapitulate in vivo responses of circulating primary cell subsets in human sepsis. Milestone-driven developmental activities in the R21 phase will focus on establishment of an efficient sample enrichment process to simultaneously collect and bank peripheral blood mononuclear cells for iPSC generation, circulating primary leukocytes and endothelial cells, and serum from whole blood. We will then generate quality-controlled iPSC lines, differentiate them into monocytes and endothelial cells, and perform functional and phenotypic characterization of patient derived cells relative to those derived from healthy donors. In the R33 phase, we will use state-of-the-art multiomic sequencing to determine if patient-specific iPSC derived cells treated with risk-stratified septic serum mirror transcriptomic and epigenomic responses of respective circulating primary cells. Scale up activities will include patient recruitment across multiple centers, standardized protocols for iPSC generation and distribution, and development of a bioinformatic database that will allow us to collate and contextualize omic analyses with rich clinical data. Through the successful execution of this proposal, we seek to transform our existing pediatric sepsis biobank to meet the needs of the next generation of scientific inquiry and facilitate cell-specific mechanistic research in human sepsis.

建立用于儿童败血症研究的患者特异性多能干细胞的多中心生物库。 项目摘要： 败血症是患有严重感染并杀死儿童比癌症的最终公共途径 每年在美国。然而，除早期抗生素和 器官支持。患者，器官和细胞水平的多种水平的异质性具有显着 尽管已使用精确医学方法来通过患者进行硅化 - 尽管 水平差异，我们从根本上缺乏对异质细胞的全面理解 反应有助于败血症发病机理。那是人类败血症生物膜的至关重要的需求 解开细胞特异性的机械途径，并加速新型败血症治疗的发展。 我们试图通过开发出患者特定诱导的多能的前所未有的生物库来弥合这一差距 源自败血症儿童的干细胞（IPSC）。人IPSC可以用作可再生和 任何细胞类型的可扩展来源，已用于众多疾病状态的精确建模。 但是，尚不清楚它们是否可以充当败血症的体外模型 - 急性状态 具有复杂的基因环境相互作用，并由宿主反应驱动。通过这个分阶段 创新奖，我们试图建立患者特异性IPSC衍生细胞捕获疾病的能力 表型和概括在人类败血症中循环原代细胞亚群的体内反应。 R21阶段中的里程碑驱动的发展活动将集中于建立有效的 样品富集过程，可轻松收集和库存外周血单核细胞的IPSC 产生，循环原代白细胞和内皮细胞，以及全血的血清。然后我们会 生成质量控制的IPSC线，将它们区分为单核细胞和内皮细胞，然后执行 相对于来自健康的细胞的患者衍生细胞的功能和表型表征 捐助者。在R33阶段，我们将使用最先进的多构测序来确定患者特定的 IPSC衍生的细胞，用风险分离化的化粪池血清镜像转录组和表观基因组反应 各自循环的原代细胞。扩大活动将包括多个中心的患者招募， IPSC生成和分发的标准化协议，以及开发生物信息学数据库 将允许我们与丰富的临床数据整理和背景化OMIC分析。通过成功 执行该提案，我们试图改变现有的儿科败血症生物库来满足 下一代的科学探究并促进了人类败血症的细胞特异性机械研究。