Sexual dimorphism in the mammalian kidney

哺乳动物肾脏的性别二态性

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要/摘要人们越来越共识，男人和女人在对肾脏损伤的反应方面有所不同，他们的对慢性肾脏疾病的敏感性和进展。类似的发现也来自对不同的分析啮齿动物模型中的性别。从历史上看，女性在动物建模和临床上的代表性不足研究。纠正这种不平衡并了解基因表达中与性别相关的差异是如何的产生以及这些如何影响哺乳动物器官系统中正常和病理作用，是一个优先事项。麦克马洪组最近的单细胞RNA-seq研究突出了广泛的性行为成年小鼠肾脏近端小管段内的二态性。近端小管细胞具有主要作用用肾脏的肝细胞对循环代谢产物的化学修饰。近端小管细胞也有肾脏在吸收，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的相似和独特的性二态基因集具有潜力激素相互作用（雄激素，雌激素，生长激素）的差异如何建立双态细胞态。怀孕和护理对女性提出了更多要求。即使在小鼠模型中，这些需求如何影响雌性肾脏中的二态细胞态也不清楚。由于缺乏人类肾脏的可比，高质量的比较数据，因此没有明确的想法人类肾脏中性二态性的程度，因此，哪种监管行为可能是与鼠标模型共享，或者是特定于人类的。在此提案中，我们将使用单个核（SN）RNA-seq， SNATAC-SEQ和遗传方法确定建立性二态细胞的调节过程小鼠肾脏中的类型，以及那些在生殖近端小管中修饰基因活性的类型过程。从全球应用单细胞技术向人类应用的努力中出现的可比数据集系统将共享共享和不同的监管过程。具体目标1将决定调节机制，包括直接激素信号传导的作用（雄激素，雌激素和生长激素），在雄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肝细胞中重叠的基因同类群体重叠的类似数据形成对比。具体的 AIM 2将确定妊娠，护理和催乳素信号的调节性相互作用。小鼠肾脏中的二态细胞态。具体目标3将将鼠标中的性二态性与人类肾脏活检，将提案中产生的数据整合到肾脏塞莱克莱普尔的框架中（https://cello.shinyapps.io/kidneycellexplorer/）用于查看和分析数据。