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 肾脏疾病是常见且致命的疾病，常在儿童期发病。肾脏和泌尿道先天性 儿童肾衰竭的大部分原因是异常。肾小球疾病和急性肾损伤 (AKI) 发生在高达 60% 的新生儿和儿科重症监护患者中，与住院时间长短直接相关 居留、随后的残疾和死亡率。儿童期肾脏损伤，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病（CKD），以及隐秘的高血压和蛋白尿。 尽管对胎儿和成人肾脏的分子检查很先进，但有关出生后发育和发育的数据 由于缺乏健康/参考的儿科样本，受伤的儿科肾脏和尿路滞后 肾脏和调查网络。该数据集对于了解所有产后肾脏疾病至关重要 活着的儿童，并加强对各种联盟的调查，询问来自儿童的分子特征 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，可以将 一组协作的研究人员与生物医学核心 (pKidBIO) 以及经过验证的捐赠者来源 儿科器官构建了一个跨越年龄、种族和性别的地图集。 pKidCAP 将应用 snRNAseq/ATACseq 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。细胞类型和状态 将使用近单细胞空间转录组学绘制整个儿科生命周期组织的多样性。 这些地图将在健康和儿童肾脏疾病活检子集上生成，可以提供信息 项目 2 和其他研究类似疾病的联盟中的疾病模型研究。全基因组 所有样本的测序将提供与离散区域相关的表达数据的链接 单细胞中的活性 DNA 位点，以解析其细胞身份的相应 SNP 或有害变异。 pKidCAP 图集将作为对重建肾脏感兴趣的研究界的基准， 阐明肾脏成熟和稳态的机制，并将 GWAS 特征映射到活跃状态 支持因果关系。使用动物模型和 iPS 细胞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。独特的数据和地图 将吸引传统肾脏研究人员之外的专业知识，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 结合从儿科到成人各个时间点的多模态数据集。机械研究人员 学习、衰老研究和组织工程将被用来解决细胞的基本问题 与疾病、衰老和组织工程相关的分化可广泛应用于其他领域 器官系统。该项目也将是吸引以下学生和学员的独特机会 着手单细胞多组学项目，从而增加该领域未来的研究人员队伍。