Retinoic acid gene regulatory networks in the mammalian kidney

项目摘要/摘要 适当的肾单位捐赠和分割对于建立健康的肾脏是必不可少的。肾单位数 在人类中是高度不同的。低肾单位数与高血压风险增加和 终末期肾病。更好地了解肾脏形成的机制将有助于我们设计出一种 增加肾单位捐赠的方法。沿近-远轴线，肾小体与 经近端小管、Henle环和远端小管收集导管。每段肾单位执行 不同的生理功能。了解多能肾单位祖细胞如何决定其细胞命运 决定发展成不同的肾单位节段不仅对建立一个功能正常的肾单位至关重要 体外也有促进肾损伤后再生的作用。在这项拟议的研究中，我们将调查 维甲酸信号转导调节肾单位的发育和分割。我们发现，在小鼠身上，抑制 间充质肾单位祖细胞维甲酸信号转导导致肾单位显著减少 天赋。我们还发现，在新形成的发育中的肾单位中，维甲酸信号的抑制 干扰近端小管细胞的形成和成熟。我们的初步数据显示维甲酸 酸性信号在肾脏形成的早期和后期起着重要作用，有助于形成合适的肾单位。 与生俱来和细分。在目标1中，通过操纵体内遗传的维甲酸信号和 在体外药理学方面，我们将测试间充质向上皮转化是否需要维甲酸信号。 肾小球祖细胞与Wnt/-Catenin信号的协同作用为了了解维甲酸是如何 信号转导参与肾单位功能，我们将确定维甲酸基因调控网络在 肾单位祖细胞。在目标2中，通过进行维甲酸的遗传功能获得和功能丧失研究 在新形成的发育中的肾单位中的酸信号，我们将测试维甲酸信号是必要的还是 足以形成和成熟近端小管。我们还将确定维甲酸基因 发育中肾单位的调节网络以了解维甲酸信号如何调节肾单位 分段。我们提出的研究将填补分子机制中长期存在的知识空白。 近端肾小管的形成或成熟是决定肾单位天赋的基础 在哺乳动物身上。我们的长期目标是设计一种方法，在发育过程中增加肾单位的捐赠 并为潜在的细胞替代疗法生成肾小管细胞。

Project Summary/Abstract Proper nephron endowment and segmentation are essential for building healthy kidneys. Nephron number is highly variable among humans. Low nephron number is associated with increased risk of hypertension and end-stage renal disease. A better understanding of the mechanisms of nephrogenesis will help us devise a way to increase nephron endowment. Along the proximal-distal axis, the renal corpuscle is connected to the collecting duct via the proximal tubule, loop of Henle, and distal tubule. Each nephron segment carries out distinct physiological functions. Understanding how multipotent nephron progenitors make their cell fate decisions to develop into different nephron segments is essential not only for building a functional nephron in vitro but also for promoting regeneration after kidney injury. In this proposed study, we will investigate how retinoic acid signaling regulates nephron endowment and segmentation. We found that, in mice, inhibition of retinoic acid signaling in mesenchymal nephron progenitor cells caused significantly lower nephron endowment. We also found that inhibition of retinoic acid signaling in the newly formed developing nephron interfered with the formation and maturation of proximal tubule cells. Our preliminary data suggest that retinoic acid signaling plays important roles in early and later stages of nephrogenesis, contributing to proper nephron endowment and segmentation. In Aim 1, by manipulating retinoic acid signaling genetically in vivo and pharmacologically in vitro, we will test if retinoic acid signaling is required for mesenchymal-to-epithelial transition of nephron progenitors by coordinating with Wnt/-catenin signaling. To understand how retinoic acid signaling contributes to nephron endowment, we will determine the retinoic acid gene regulatory network in nephron progenitors. In Aim 2, by performing genetic gain-of-function and loss-of-function studies of retinoic acid signaling in the newly formed developing nephron, we will test if retinoic acid signaling is necessary or sufficient for the formation and maturation of proximal tubules. We will also determine the retinoic acid gene regulatory network in the developing nephrons to understand how retinoic acid signaling regulates nephron segmentation. Our proposed studies will fill a longstanding gap of knowledge in the molecular mechanisms underlying the determination of nephron endowment as well as the formation or maturation of proximal tubules in mammals. Our long-term goals are to devise a way to increase nephron endowment during development and to generate nephron tubule cells for potential cell replacement therapy.