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

研究项目 1：健康和患病人类儿童肾脏的多维分子图谱

• 批准号: 10530270
• 负责人: Sanjay Jain
• 金额: $ 29.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530270
• 关键词: ATAC-seq; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Age; Aging; Anatomy; Animal Model; Architecture; Atlases; Benchmarking; Biopsy; Birth; Bladder; Cardiovascular Diseases; Cause of Death; Cell Nucleus; Cells; Cessation of life; Child; Childhood; Childhood Injury; Chromatin; Chronic Kidney Failure; Clinical; Communities; Coupled; DNA; Data; Data Set; Disease; Disease model; Drug Design; Early Diagnosis; Embryo; End stage renal failure; Environment; Environmental Exposure; Epigenetic Process; Etiology; Focal Segmental Glomerulosclerosis; Functional disorder; Future; Gene Expression; Generations; Genes; Genomics; Growth; Histologic; Homeostasis; Human; Hyperoxia; Hypertension; Impairment; Infection; Intensive Care; Investigation; Ischemia; Kidney; Kidney Calculi; Kidney Diseases; Kidney Failure; Knowledge; Length of Stay; Life Cycle Stages; Link; Longevity; Lower urinary tract; Machine Learning; Maps; Methods; Molecular; Molecular Profiling; Neonatal; Organ; Organoids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient Care; Pharmaceutical Preparations; Physiological; Population; Procedures; Process; Proteinuria; Protocols documentation; Puberty; Quality Control; Quality of life; RNA; Race; Regulatory Element; Renal function; Renal glomerular disease; Research; Research Personnel; Research Project Grants; Resources; Sampling; Second Pregnancy Trimester; Sex Differences; Site; Source; Specimen; Standardization; Structure; Students; Study models; System; Technology; Therapeutic; Time; Tissue Engineering; Tissues; Tubular formation; Urinary tract; Variant; age group; analytical tool; body system; cell type; clinical phenotype; cohort; congenital anomalies of the kidney; congenital anomaly; data mining; design; disability; extracellular; fetal; gene regulatory network; genome sequencing; genome wide association study; human disease; induced pluripotent stem cell; innovation; insight; interest; kidney biopsy; kidney dysfunction; mortality; multidimensional data; multimodal data; multimodality; multiple omics; nephrogenesis; nephrotoxicity; outcome prediction; postnatal; postnatal period; preservation; quality assurance; recurrent infection; repaired; sex; trait; transcriptomics; whole genome

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.

摘要/项目摘要 肾脏疾病是常见的，致命的，童年时期经常发作。肾脏和尿路先天性 异常解释儿童的大部分肾衰竭。肾小球疾病和急性肾脏损伤 （AKI）在多达60％的新生儿和小儿重症监护患者中发生，直接与长度相关 留下，随后的残疾和死亡率。童年时期的肾脏侮辱包括缺血，高氧，感染 和肾毒性药物/环境暴露会损害肾小球，管状和膀胱生理成熟 和功能导致明显的慢性肾脏疾病（CKD），并具有隐形的高血压和蛋白尿。 尽管对胎儿和成人肾脏的分子询问是先进的，但有关产后发展的数据和 由于缺乏健康 /参考的小儿样本，小儿肾脏和尿路受伤 肾脏和调查网络。该数据集对于了解所有人的产后肾脏疾病至关重要 活着的孩子并增加对各种财团的调查，从 患有CKD的孩子。这个儿科肾脏图集项目（PKIDCAP）是团结起来的独特机会 合作组合的研究人员以及生物医学核心（PKIDBIO），并具有良好的捐助者来源 小儿器官在年龄，种族和性别之间建造一个地图集。 PKIDCAP将对SNRNASEQ/ATACSEQ应用 定义来自同一细胞的细胞特异性基因表达和顺式调节元件。细胞类型和状态 使用近单个细胞空间转录组学在组织上的小儿生命周期中，多样性将在整个小儿生命周期中进行映射。 这些地图将在健康和一部分儿科肾脏疾病活检中产生 项目2和其他研究类似疾病的疾病模型研究。全基因组 所有样本中的测序将提供与离散区域相关的表达数据的链接 单个细胞中的活性DNA位点可将相应的SNP或有害变体解析为其细胞身份。 PKIDCAP地图集将成为有兴趣重建肾脏的研究社区的基准， 阐明肾脏成熟和稳态的机制，并将GWAS特征映射到主动状态 支持因果关系。使用IPS细胞的动物模型和类器官的研究将使用该数据集作为钥匙 参考与小儿肾脏疾病有关的药物设计研究的优先级。独特的数据和地图 将在传统肾脏研究人员之外吸引专业知识，包括计算生物学家和 信息专家，设计更好的分析工具和新发现的新发现方法的新方法 从小儿到成人年龄的时间点结合多模式数据集。机器研究人员 学习，衰老研究和组织工程将被吸引以解决细胞的基本方面 与疾病，衰老和组织工程有关的分化可能广泛适用于其他 器官系统。该项目也将是吸引那些吸引学生和受训者的独特机会 启动单细胞多组学项目，从而增加了该领域的研究人员的未来人群。