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 异常占儿童肾衰竭的大多数。肾小球疾病与急性肾损伤 (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、随后的残疾和死亡率。儿童期肾损害包括缺血、高氧、感染 肾毒性药物/环境暴露损害肾小球、肾小管和膀胱的生理成熟 和功能，导致明显的慢性肾病（CKD），并与隐形高血压和蛋白尿。 尽管胎儿和成人肾脏的分子研究已经取得了进展，但关于出生后发育和 由于缺乏健康/参考的儿科样本， 肾脏和一个调查网络。该数据集对于了解所有出生后肾脏疾病至关重要 活的孩子，并加强调查各种财团询问分子签名， 儿童CKD这个儿科肾脏图谱项目（pKidCAP）是一个独特的机会， 一组协作的研究者与一个生物医学核心（pKidBIO）一起，具有经证实的供体来源 儿科器官来建立一个跨越年龄、种族和性别的图谱。pKidCAP将snRNAseq/ATACseq应用于 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 将使用近单细胞空间转录组学在组织上绘制儿科生命周期的多样性。 这些图谱将在健康和儿科肾脏疾病活检子集上生成， 项目2和其他研究类似疾病的联合体中的疾病模型研究。全基因组 所有样品中的测序将提供与DNA上的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，以解决相应的SNP或有害的变体，以他们的细胞身份。 pKidCAP图谱将作为对重建肾脏感兴趣的研究团体的基准， 阐明肾脏成熟和稳态的机制，并将GWAS特征映射到活动状态， 支持因果关系。使用动物模型和来自iPS细胞的类器官的研究将使用该数据集作为关键 优先考虑与儿科肾脏疾病相关的药物设计研究的参考。独特的数据和地图 将吸引传统肾脏研究人员以外的专业知识，包括计算生物学家， 信息学家设计更好的分析工具和新的数据挖掘方法， 将从儿童到成人年龄的时间点的多模态数据集相结合。机器研究人员 学习，衰老研究和组织工程将被吸引来解决细胞的基本方面， 与疾病、衰老和组织工程有关的差异，可以广泛适用于其他 器官系统。这个项目也将是一个独特的机会，以吸引学生和学员谁是 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。