Sexual dimorphism in the mammalian kidney

项目总结/摘要 越来越多的人认为，男性和女性对肾损伤的反应不同， 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，女性在动物建模和临床研究中的代表性不足。 问题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产生的。 产生的，以及这些如何影响哺乳动物器官系统内的正常和病理行为，是一个 要务McMahon小组最近的单细胞RNA-seq研究强调了广泛的性功能。 成年小鼠肾脏近端小管节段内的二型性。近端小管细胞在 用肾脏的肝细胞化学修饰循环代谢物。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异性作用。比较 分析显示，肝脏和肾脏之间既有相似的，也有不同的性二态基因组， 激素相互作用的差异（雄激素，雌激素，生长激素）是每个器官如何 建立二态细胞状态。特别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中的二型细胞状态尚不清楚，即使在小鼠模型中也是如此。 由于缺乏人体肾脏的可比性、高质量、可比较的数据， 性二型在人类肾脏的程度，因此，哪些调节作用可能是 与小鼠模型共享，或者是人类特异性的。在这项提案中，我们将使用单核（sn）RNA-seq， snATAC-seq和遗传学方法来确定建立性二态细胞的调控过程 小鼠肾脏中的基因型，以及在生殖系统中近端小管细胞内修饰基因活性的基因型。 过程将单细胞技术应用于人类的全球努力中出现的可比数据集 系统将共同分析共享和不同的监管流程。具体目标1将决定 调节机制，包括直接激素信号（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 将与性二态肝细胞内重叠基因组的类似数据进行对比。具体 目的2将确定妊娠、哺乳和催乳素信号在改变性行为中的相互调节作用。 小鼠肾脏中的二型细胞状态。具体目标3将比较小鼠的性二态性与 人类肾脏活检，将提案中产生的数据整合到KidneyCellExplorer框架中 （https：//cello.shinyapps.io/kidneycellexplorer/），用于查看和分析数据。

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.