Research Project 1: A Multidimensional Molecular Atlas of Healthy and Diseased Human Pediatric Kidney

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 异常是儿童肾功能衰竭的主要原因。肾小球疾病与急性肾损伤 (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、随后的残疾和死亡。儿童时期的肾脏损害，包括缺血、高氧、感染 肾毒性药物/环境暴露会损害肾小球、肾小管和膀胱的生理成熟 和功能导致明显的慢性肾脏疾病(CKD)，并伴有更隐蔽的高血压和蛋白尿。 虽然对胎儿和成人肾脏的分子询问是先进的，但关于出生后发育和 儿童肾脏和尿路损伤因缺乏健康/参考的儿科样本而滞后 肾脏和一个调查网络。这一数据集对于全面了解出生后肾脏疾病至关重要 并加强对询问儿童分子特征的各种财团的调查 患有CKD的儿童。这个儿科肾脏图谱项目(PKidCAP)是一个独特的机会，可以联合 一组合作的研究人员，以及一个生物医学核心(PKidBIO)，具有公认的捐赠者来源 建立跨年龄、种族和性别的儿科器官地图集。PKidCAP将应用SnRNAseq/ATACseq用于 定义来自同一细胞的细胞特异性基因表达和顺式调控元件。单元格类型和状态 利用近乎单细胞的空间转录，将在整个儿科生命周期中绘制组织的多样性图谱。 这些地图将在健康和儿童肾脏疾病活检的子集上生成，可以为 在项目2和其他研究类似疾病的联合体中进行的疾病模型研究。全基因组 所有样本中的测序将提供与基因上离散区域相关的表达数据的链接 在单个细胞中的活性DNA位点，以解析相应的SNPs或有害变异体的细胞身份。 PKidCAP图谱将成为对重建肾脏感兴趣的研究界的基准， 阐明肾脏成熟和动态平衡的机制，并将GWA型性状定位到活跃状态 支持因果关系。使用来自iPS细胞的动物模型和有机化合物的研究将使用该数据集作为关键 与儿童肾脏疾病相关的药物设计优先研究的参考。唯一的数据和地图 将吸引传统肾脏研究人员以外的专业人士，包括计算生物学家和 信息学家为新发现设计更好的分析工具和新的数据挖掘方法 结合从儿童到成人年龄的时间点的多模式数据集。机器中的研究人员 学习、衰老研究和组织工程学将被用来解决细胞的基本方面 与疾病、衰老和组织工程有关的辨证可能广泛适用于其他 器官系统。该项目也将是一个独特的机会，吸引学生和实习生谁是 开展单细胞多组学项目，从而增加该领域未来的研究人员队伍。

Abstract/Project Summary Kidney disease is common and deadly with frequent onset in childhood. Kidney and urinary tract congenital anomalies account for the majority of renal failure in children. Glomerular diseases and acute kidney injury (AKI) occur in up to 60% of neonatal and pediatric intensive care patients, directly correlating with length of stay, subsequent disability, and mortality. Kidney insults in childhood including ischemia, hyperoxia, infection and nephrotoxic drug/environmental exposures impair glomerular, tubular and bladder physiologic maturation and function resulting in overt chronic renal disease (CKD), and with stealthier hypertension and proteinuria. Although molecular interrogation of fetal and adult kidney is advanced, data on the postnatal developing and injured pediatric kidney and urinary tract are lagging due to lack of pediatric samples of healthy / reference kidneys and a network for investigation. This dataset is critical to understand postnatal kidney disease in all living children and to augment investigation of various consortia interrogating molecular signatures from children with CKD. This pediatric kidney atlas project (pKidCAP) is a unique opportunity to unite a collaborative set of investigators together with a biomedical core (pKidBIO) with a proven source of donor pediatric organs to build an atlas across age, race and sex. The pKidCAP will apply snRNAseq/ATACseq for defining cell specific gene expression and cis-regulatory elements from the same cell. Cell type and state diversity will be mapped across the pediatric life cycle on tissue using near single cell spatial transcriptomics. These maps will be generated on healthy and a subset of pediatric kidney disease biopsies that can inform disease model studies in Project 2 and other consortia investigating similar diseases. Whole genome sequencing in all of the samples will provide a link of expression data associated with discrete regions on the active DNA site in single cells to resolve corresponding SNPs or deleterious variants to their cell identities. The pKidCAP atlas will serve as a benchmark for the research community interested in rebuilding kidneys, elucidating mechanisms of kidney maturation and homeostasis, and mapping GWAS traits to active states to support causality. Studies using animal models and organoids from iPS cells will use this dataset as a key reference to prioritize research for drug design relevant to pediatric kidney disease. The unique data and maps will attract expertise outside traditional kidney researchers, including computational biologists and informaticists to design better analytical tools and new methods of data mining for new discoveries by combining multimodal datasets across time points from pediatric to adult ages. Researchers in machine learning, ageing research and tissue engineering will be drawn to solve fundamental aspects of cellular differentiation in relation to disease, ageing and tissue engineering that could be broadly applicable to other organ systems. This project will also be a unique opportunity to attract students and trainees who are embarking on single cell multiomics projects, thereby increasing the future cohort of researchers in this field.