Sexual dimorphism in the mammalian kidney

项目摘要/摘要 越来越多的人达成共识，即男性和女性对肾脏损伤的反应不同，而且他们的 慢性肾脏疾病的易感性和进展。类似的发现来自于对不同的 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中的比例一直偏低 学习。纠正这种不平衡，并理解基因表达的性别差异是如何 以及这些如何影响哺乳动物器官系统内的正常和病理活动，是一个 优先考虑。最近麦克马洪小组的单细胞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形性。近端肾小管细胞起主要作用 用肾脏的肝细胞对循环代谢产物进行化学修饰。近端小管细胞也有 肾脏在吸收、运输和清除有益或有害分子方面的特殊作用。比较 分析表明，肝脏和肾脏之间存在相似和不同的性别二态基因集，具有潜在的 不同的激素相互作用(雄激素、雌激素、生长激素)如何影响每个器官 建立两种形态的细胞状态。具体来说，怀孕和哺乳对女性提出了额外的要求。 这些需求如何影响女性肾脏中的二态细胞状态尚不清楚，即使在小鼠模型中也是如此。 由于缺乏可比的、高质量的人类肾脏对比数据，目前还没有明确的概念。 人类肾脏中性二型性的程度，因此，哪些调节行动可能是 与老鼠模型共享，或者是人类特有的。在本提案中，我们将使用单核(SN)RNA-seq， SNATAC-SEQ和遗传学方法确定建立性二形态细胞的调控过程 在小鼠肾脏中的类型，以及在生殖中近端小管细胞内改变基因活性的那些 进程。来自全球将单细胞技术应用于人类的可比数据集 将针对共享的和不同的监管流程对系统进行共同分析。具体目标1将决定 调节机制，包括直接激素信号的作用(雄激素、雌激素和生长 激素)，在雄性和雌性小鼠肾脏中产生不同类型的近端小管细胞。肾脏数据集 将与性别二型性肝细胞内重叠基因队列的类似数据形成对比。特定的 目标2将确定怀孕、哺乳和催乳素信号在变性过程中的调节相互作用 小鼠肾脏中的二态细胞状态。《特定目标3》将比较小鼠的性二型性和 人类肾脏活检，将提案中产生的数据整合到KidneyCellExplorer框架中 用于查看和分析数据的(https://cello.shinyapps.io/kidneycellexplorer/)。

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.