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.

建立患者特异性多能干细胞多中心生物库，用于儿科脓毒症研究。 项目概要： 脓毒症是严重感染者的最后共同途径，导致的儿童死亡人数比癌症还要多 然而，在美国，除了早期抗生素和治疗外，没有其他治疗方法可用于治疗儿童脓毒症。 器官支持在患者、器官和细胞水平上具有显着的多层次异质性。 尽管精准医学方法已被用来筛选患者。 由于水平差异，我们从根本上缺乏对异质细胞如何 因此，人类脓毒症生物库迫切需要 揭示细胞特异性机制途径并加速新型脓毒症治疗方法的开发。 我们寻求通过开发前所未有的患者特异性诱导多能生物库来弥补这一差距 源自脓毒症儿童的干细胞（iPSC）可用作可再生的和可再生的。 任何细胞类型的可扩展来源，并已用于多种疾病状态的精确建模。 然而，目前尚不清楚它们是否可以作为脓毒症（一种急性疾病）的可靠体外模型 复杂的基因-环境相互作用，并主要由宿主反应驱动。 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 表型并概括了人类败血症中循环原代细胞亚群的体内反应。 R21阶段里程碑驱动的发展活动将侧重于建立高效的 样品富集过程，同时收集和储存外周血单核细胞用于 iPSC 然后我们将生成全血、循环原代白细胞和内皮细胞以及血清。 生成质量控制的 iPSC 系，将其分化为单核细胞和内皮细胞，并执行 患者来源的细胞相对于健康来源的细胞的功能和表型特征 在 R33 阶段，我们将使用最先进的多组学测序来确定患者是否具有特异性。 用风险分层脓毒症血清处理的 iPSC 衍生细胞反映了以下疾病的转录组和表观基因组反应： 各自的循环原代细胞的扩大活动将包括跨多个中心的患者招募， iPSC 生成和分发的标准化协议，以及生物信息数据库的开发 将使我们能够通过成功的临床数据来整理和背景化组学分析。 执行该提案，我们寻求改造现有的儿科脓毒症生物库，以满足 下一代科学探究并促进人类脓毒症的细胞特异性机制研究。