Pediatric Kidney Single Cell Atlas Project

摘要/项目摘要 肾脏疾病是一种常见且致命的疾病，常在儿童时期发病。先天性肾和尿路 畸形是儿童肾功能衰竭的主要原因，此外，继发性急性肾损伤也是主要原因。 (AKI)发生在高达60%的新生儿和儿童重症监护患者中，与持续时间直接相关 留下来，随后的残疾，以及早期死亡。儿童时期的肾脏损伤包括缺血，高氧， 感染和肾毒性药物/环境暴露损害肾脏成熟和功能，导致 慢性肾脏疾病(CKD)以及更隐蔽的高血压、肾结石和蛋白尿。最新进展 肾脏疾病早期发现和严重程度测量的有效干预和方法 儿童落后的部分原因是缺乏对发生在 肾脏成熟。分子蓝图将极大地增强我们设计有效 干预和预防肾功能障碍的方法。然而，如果没有一个 儿科肾脏组织来源开始分子讯问以识别独一无二的人类和 制造和维持健康肾脏所需的发育指令。该计划的目标是 华盛顿大学肾脏单细胞图谱项目(PKidCAP)是为创建一个极具独特性和创新性的 儿科卓越中心，通过空间提供新的概念、知识和资源 儿童参考肾脏和病变肾脏在多个时间点的可分辨单细胞分子图谱 儿科的寿命。PKidCAP调查人员将应用配对的SnRNAseq、SnATACseq技术 解码同一细胞中的基因调控和表达，并使用空间转录组学来解决 从儿童肾脏获取的健康和疾病样本的细胞多样性和形态 生物医学核心和小鼠肾小球疾病模型。教育和机会池计划 将通过以下方式促进儿科肾脏疾病研究的热情和进步：1)提供针对特定年龄的人类 胎儿和儿童肾脏疾病组织的参考文献，2)使旨在描绘细胞的研究成为可能， 与出生后肾脏成熟相关的形态、生理和分子变化，3) 加快针对体外人肾有机化合物的科学研究，4)建立分离方案 分化的肾细胞类型与肾组织样本中看到的阶段一致，5)进展 药物毒性筛选，并通过设计基因功能和肾脏工程的验证研究。这个 组织的可用性和由此产生的杰出数据将吸引肾脏以外的新专业人员 发展中的空间成像和分析技术以及对生理衰老感兴趣的研究 在整个生命周期内。

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.