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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

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.

项目总结/文摘