Sexual dimorphism in the mammalian kidney

哺乳动物肾脏的性别二态性

• 批准号: 10654566
• 负责人: ANDREW P. MCMAHON
• 金额: $ 60.33万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654566
• 关键词: ATAC-seq; Address; Adopted; Adult; Anatomy; Androgens; Animal Model; Atlases; Attention; Biological Models; Biopsy; Cells; Chemicals; Chronic Kidney Failure; Clinical Data; Clinical Research; Communities; Consensus; Data; Data Analyses; Data Set; Discipline of Nursing; Environment; Estrogens; Estrus; Evolution; Excision; Female; Gene Expression; Genes; Genetic; Genetic study; Glomerular Filtration Rate; Gonadal structure; Hepatocyte; Hormonal; Hormonal Change; Hormone Receptor; Hormones; Human; In Situ Hybridization; Injury to Kidney; International; Kidney; Kidney Transplantation; Liver; Maps; Mediating; Modification; Molecular; Molecular Profiling; Mus; Nephrons; Normal tissue morphology; Nuclear RNA; Organ; Outcome; Outcome Measure; Overlapping Genes; Pathologic; Pathway interactions; Physiological; Play; Potassium; Predisposition; Pregnancy; Process; Prolactin; Reproduction; Reproductive Process; Reproductive system; Research Design; Rodent Model; Role; Sex Differences; Signal Transduction; Sodium; Somatotropin; Source; Sterile coverings; System; United States National Institutes of Health; Weaning; Woman; body system; cell type; cohort; comparative; complex data; data integration; genetic approach; hormonal signals; human data; kidney biopsy; kidney cell; kidney repair; kidney surgery; male; men; mouse model; postnatal; programs; response; sex; sexual dimorphism; sexual role; single cell technology; single-cell RNA sequencing; systems research; transcriptome sequencing

Project Summary/Abstract There is a growing consensus that men and women differ in their response to kidney injury, and their susceptibility and progression to chronic kidney disease. Similar findings have come from the analysis of different sexes in rodent models. Historically, females have been under-represented in animal modeling and clinical studies. Redressing this imbalance and understanding how sex-related differences in gene expression are generated, and how these influence normal and pathological actions within mammalian organ systems, is a priority. Recent single cell RNA-seq studies in the McMahon group have highlighted extensive sexual dimorphism within proximal tubule segments of the adult mouse kidney. Proximal tubule cells share a major role in chemical modification of circulating metabolites with hepatocytes of the kidney. Proximal tubule cells also have kidney specific actions in resorption, transport and removal of beneficial or harmful molecules. Comparative analysis shows both similar and distinct sexually dimorphic gene sets between the liver and kidney, with potential differences in hormonal interplay (androgens, estrogens, growth hormone) underlying how each organ establishes dimorphic cell states. Pregnancy and nursing present additional demands on the female, specifically. How these demands may impact dimorphic cell states in the female kidney is not clear, even in the mouse model. Due to the absence of comparable, high quality, comparative data for the human kidney, there is no clear idea of the extent of sexual dimorphism in the human kidney, and consequently, which regulatory actions may be shared with mouse models, or are human specific. In this proposal, we will use single nuclear (sn)RNA-seq, snATAC-seq and genetic approaches to determine the regulatory processes establishing sexually dimorphic cell types in the mouse kidney, and those modifying gene activity within proximal tubule cell in the reproductive process. Comparable datasets emerging from worldwide efforts applying single cell technologies to human systems will be co-analyzed for shared and distinct regulatory processes. Specific Aim 1 will determine regulatory mechanisms, including the action of direct hormone signaling (androgens, estrogen and growth hormone), in generating distinct proximal tubule cell types in the male and female mouse kidney. Kidney datasets will be contrasted with similar data for overlapping gene cohorts within sexually dimorphic hepatocytes. Specific Aim 2 will determine the regulatory interplay of pregnancy, nursing and prolactin signaling in modifying sexually dimorphic cell states in the mouse kidney. Specific Aim 3 will compare sexual dimorphism in the mouse with human kidney biopsies, integrating data generated in the proposal into the framework of KidneyCellExplorer (https://cello.shinyapps.io/kidneycellexplorer/) for viewing and analysis of the data.

项目概要/摘要 人们越来越认识到，男性和女性对肾损伤的反应不同，而且他们的肾功能也不同。 慢性肾脏病的易感性和进展。类似的发现来自不同的分析 啮齿动物模型中的性别。从历史上看，女性在动物模型和临床研究中的代表性不足 研究。纠正这种不平衡并了解基因表达中性别相关的差异是如何产生的 产生，以及它们如何影响哺乳动物器官系统内的正常和病理行为，是一个 优先事项。 McMahon 小组最近的单细胞 RNA-seq 研究强调了广泛的性行为 成年小鼠肾脏近端小管段内的二态性。近曲小管细胞起着重要作用 用肾脏肝细胞对循环代谢物进行化学修饰。近曲小管细胞还具有 肾脏在吸收、运输和去除有益或有害分子方面的特定作用。比较 分析显示肝脏和肾脏之间存在相似和不同的性二态性基因组，具有潜在的潜力 每个器官的荷尔蒙相互作用（雄激素、雌激素、生长激素）的差异 建立二态细胞状态。尤其是怀孕和哺乳对女性提出了额外的要求。 这些需求如何影响雌性肾脏的二态性细胞状态尚不清楚，即使在小鼠模型中也是如此。 由于缺乏人类肾脏的可比、高质量的比较数据，目前尚无明确的想法 人类肾脏性别二态性的程度，以及因此可能采取的监管措施 与小鼠模型共享，或者是人类特有的。在这个提案中，我们将使用单核（sn）RNA-seq， snATAC-seq 和遗传方法确定建立性二态性细胞的调控过程 小鼠肾脏中的类型，以及在生殖系统中改变近端小管细胞内基因活性的类型 过程。全球范围内将单细胞技术应用于人类的努力中出现的可比数据集 系统将针对共享和不同的监管流程进行共同分析。具体目标 1 将确定 调节机制，包括直接激素信号传导（雄激素、雌激素和生长激素）的作用 激素），在雄性和雌性小鼠肾脏中产生不同的近端小管细胞类型。肾脏数据集 将与性二态性肝细胞内重叠基因组的类似数据进行对比。具体的 目标 2 将确定妊娠、哺乳和催乳素信号在性改变中的调节相互作用 小鼠肾脏中的二态性细胞状态。具体目标 3 将比较小鼠的性别二态性 人类肾脏活检，将提案中生成的数据整合到 KidneyCellExplorer 的框架中 (https://cello.shinyapps.io/kidneycellexplorer/) 用于查看和分析数据。