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.

建立一个多中心的患者特异性多能干细胞生物库用于儿科脓毒症研究。 项目概要： 脓毒症是严重感染者的最终共同途径，比癌症杀死更多的儿童 在美国，每年。然而，除了早期的抗生素治疗， 器官支持。在患者、器官和细胞水平上的多个水平的异质性显著地影响了 阻碍了科学进步。尽管精准医疗方法已被用于筛选患者- 水平的差异，我们从根本上缺乏对异质性细胞如何 反应有助于脓毒症发病机制。因此，迫切需要人脓毒症生物储存库， 阐明细胞特异性机制途径，加速新型脓毒症治疗剂的开发。 我们试图通过开发一个前所未有的患者特异性诱导多能干细胞生物库来弥合这一差距。 干细胞（iPSC）来源于败血症儿童。人iPSC可以用作可再生的和可再生的生物材料。 它是任何细胞类型的可扩展来源，并已用于许多疾病状态的精确建模。 然而，目前还不清楚它们是否可以作为脓毒症（一种急性疾病）的体外模型。 具有复杂的基因与环境相互作用，主要由宿主反应驱动。通过这一阶段 创新奖，我们寻求建立患者特异性iPSC衍生细胞捕获疾病的能力 表型和概括在人败血症中循环原代细胞亚群的体内应答。 R21阶段的里程碑驱动的发展活动将侧重于建立一个有效的 同时收集和储存用于iPSC的外周血单核细胞的样品富集过程 生成、循环原代白细胞和内皮细胞以及来自全血的血清。然后我们将 产生质量受控的iPSC系，将它们分化成单核细胞和内皮细胞，并进行 患者来源的细胞相对于健康人来源的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组测序来确定患者特异性 用风险分层的脓毒症血清处理的iPSC衍生的细胞镜像转录组学和表观基因组学应答 各自的循环原细胞。扩大活动将包括在多个中心招募患者， iPSC生成和分配的标准化方案，以及开发生物信息学数据库， 将使我们能够整理和情境化具有丰富临床数据的组学分析。通过成功 执行这项建议，我们寻求改造我们现有的儿科脓毒症生物库，以满足需求， 下一代的科学探究和促进人类脓毒症的细胞特异性机制研究。