Pediatric Kidney Single Cell Atlas Project

摘要/项目摘要 肾脏疾病是一种常见的致命疾病，经常在儿童时期发病。先天性肾和泌尿道 异常占大多数的肾功能衰竭的儿童，此外，继发性急性肾损伤， (AKI)发生在高达60%的新生儿和儿科重症监护患者中，与病程长短直接相关。 住院、随后残疾和早期死亡。儿童期肾脏损伤包括缺血、高氧， 感染和肾毒性药物/环境暴露损害肾成熟和功能， 慢性肾脏病（CKD）和隐匿性高血压、肾结石和蛋白尿。发展 有效的干预措施和方法的早期发现和严重程度的测量， 儿童在这方面的落后，部分原因是缺乏对生理和病理变化的了解， 肾脏就会成熟分子蓝图将极大地增强我们设计有效的 干预和预防肾功能障碍的方法。然而，如果没有一个 儿科肾脏组织的来源，开始分子询问，以确定独特的人类和 发育和维持健康肾脏所需的经济学指导。的目的 华盛顿大学肾脏单细胞图谱项目（pKidCAP）是一个高度独特和创新的 儿科卓越中心，通过提供空间， 在多个时间点解析儿科参考和患病肾脏的单细胞分子图谱 儿童的寿命pKidCAP研究人员将应用配对snRNAseq、snATACseq技术， 解码来自同一细胞的基因调控和表达，并使用空间转录组学来解决 使用来自儿科肾脏的健康和疾病样本的细胞多样性和形态学， 生物医学核心和肾小球疾病的小鼠模型。教育和机会池计划 将通过以下方式促进儿童肾脏疾病研究的热情和进展：1）提供人类年龄特异性 胎儿和儿童肾脏疾病组织的参考，2）能够进行旨在描绘细胞， 与出生后肾脏成熟相关的形态、生理和分子变化，3） 加速针对离体人类肾脏类器官的科学研究，4）建立用于分离的方案， 分化的肾细胞类型，其阶段与肾组织样本中观察到的阶段一致，5）进展 药物毒性筛选，以及6）设计基因功能和肾脏工程的验证研究。的 组织的可用性和从中产生的优秀数据将吸引肾脏以外的新专业知识 研究开发空间成像和分析技术以及对生理老化感兴趣的研究 在整个生命周期中。

Abstract/Project Summary Kidney disease is common and deadly with frequent onset in childhood. Kidney and urinary tract congenital anomalies account for most of the renal failure in children while, in addition, secondary acute kidney injury (AKI) occurs in up to 60% of neonatal and pediatric intensive care patients, directly correlating with length of stay, subsequent disability, and with early mortality. Kidney insults in childhood including ischemia, hyperoxia, infection and nephrotoxic drug/environmental exposures impair kidney maturation and function resulting in chronic renal disease (CKD) and with stealthier hypertension, renal stones and proteinuria. The development of effective interventions and methods of early detection and severity measurements of renal disease in children is lagging in part due to a lack of knowledge of physiological and pathological changes that occur as the kidney matures. Molecular blueprints would dramatically enhance our ability to design effective approaches to intervene and prevent kidney dysfunction. This goal cannot be met, however, without having a source of pediatric kidney tissue to begin molecular interrogations to identify the uniquely human and developmental, ’omic instructions required to make and maintain healthy kidneys. The objective of the Washington University Kidney Single Cell Atlas Project (pKidCAP) is to create a highly unique and innovative Pediatric Center of Excellence that delivers novel concepts, knowledge and resources by providing spatially resolved single cell molecular maps of pediatric reference and diseased kidneys at several time points across the pediatric lifespan. The pKidCAP investigators will apply paired snRNAseq, snATACseq technologies for decoding gene regulation and expression from the same cell and use spatial transcriptomics to resolve the cellular diversity with morphology using healthy and disease samples from pediatric kidneys procured from the Biomedical core and in mouse model of glomerular disease. The educational and opportunity pool programs will promote enthusiasm and progress in pediatric kidney disease research by 1) providing human age-specific references for fetal and childhood kidney disease tissues, 2) enabling studies aimed to delineate cellular, morphological, physiological and molecular changes associated with postnatal kidney maturation, 3) accelerating scientific research aimed at ex vivo human kidney organoids, 4) establishing protocols for isolating differentiated kidney cell types at stages consistent with those seen in kidney tissue samples, 5) advancing drug toxicity screening, and by 6) designing validation studies of gene function and kidney engineering. The availability of the tissue and the outstanding data generated from them will attract new expertise outside kidney research developing spatial imaging and analytical technologies and research interested in physiological aging across the lifespan.