Von Hippel-Lindau mediates nephron progenitor fate via regulation of metabolism

项目摘要/摘要： 先天性肾脏结构异常是终末期肾病(ESRD)的主要原因，并导致 发病率和死亡率增加的风险。正常的肾单位(肾脏的功能单位)的发育至关重要。 以维持肾脏的正常功能和动态平衡。先天性肾脏异常通常源于 由于肾单位发育异常导致肾单位的丧失。肾功能的丧失与 重大疾病，如终末期肾病易感性。导致肾单位数量减少的一种侮辱是 病理性缺氧。VHL/HIF途径是发育过程中表达的主要氧感受途径。 肾脏。在正常的肾脏发育过程中，血管成熟有助于氧气的增加。 集中精神。在分子上，这个过程允许泛素连接酶冯·希佩尔·林道的招募 在肾单位祖细胞中标记低氧诱导因子1α(HIF-1α)以进行蛋白酶体降解。 我们认为，这种严格调控的途径在一定程度上是正常肾单位发育的原因。 此外，最近的研究表明，肾单位祖细胞的代谢特征决定了命运 糖酵解有利于自我更新，而线粒体呼吸导致分化。基座 根据这些最近的发现，我认为VHL是代谢转换和肾单位的关键介质。 祖先命运的决定。 为了验证我的假设，我的实验室建立了一个有条件删除VHL的小鼠模型 在肾单位祖细胞(VHLNP-/-)。我有初步数据表明组织缺陷和肾脏 最早出现在胚胎15.5天(E15.5)的畸形。我们的小鼠模型丧失了生存能力 出生后第28天左右(P28)，肾功能下降。RNA测序使用分离的 E17.5VHLNP-/-的肾单位祖细胞及其代谢关键基因的异常调节 (显著上调糖酵解基因)。此外，我发现VHLNP-/-肾祖细胞仍然存在 即使在出生后随时可以获得氧气的情况下也会发生糖酵解。为了继续这项调查，我提出了两个目标 1)确定VHL是否介导糖酵解和线粒体呼吸之间的转换 信号肾祖细胞分化；2)VHL和VHL之间的相互作用 线粒体在肾单位祖细胞命运中的决定作用。这些发现将证明严格 VHL的发育调节，并为肾脏疾病的治疗确定新的治疗靶点。好了！

Project Summary/Abstract: Congenital structural kidney abnormalities are a major cause of end stage kidney disease (ESRD) and lead to increased risk of morbidity and mortality. Normal nephron (functional unit of the kidney) development is crucial for proper function and homeostasis maintenance in the kidney. Congenital kidney abnormalities often stem from aberrant nephron development resulting in a loss of nephrons. Loss of nephrons has been linked to significant disease such as ESRD susceptibility. One insult that causes decreased nephron number is pathological hypoxia. The VHL/HIF pathway is the major oxygen-sensing pathway expressed in the developing kidney. During normal kidney development, vasculature maturation facilitates increases in oxygen concentration. Molecularly, this process allows for the recruitment of the ubiquitin ligase von Hippel Lindau (VHL) in the nephron progenitors to mark hypoxia-inducible factor 1α (HIF-1α) for proteasomal degradation. We believe this tightly regulated pathway is, in part, responsible for normal nephron development. Furthermore, it has recently been shown that the metabolic profile of nephron progenitors dictates fate decisions such that glycolysis favors self-renewal while mitochondrial respiration leads to differentiation. Based on these recent findings, I believe that VHL is a critical mediator of metabolic switching and nephron progenitor fate decisions. To interrogate my hypothesis, my lab generated a mouse model with a conditional deletion of VHL specifically in the nephron progenitors (VHLNP-/-). I have preliminary data indicating histological defects and renal malformations that appear as early as embryonic day 15.5 (E15.5). Loss of viability of our mouse model occurs around postnatal day 28 (P28) after a reduction in renal function. RNA-sequencing was done using isolated nephron progenitors from E17.5 VHLNP-/- and revealed dysregulation of key genes involved in metabolism (significantly up-regulated glycolysis genes). Additionally, I discovered VHLNP-/- nephron progenitors remain glycolytic even after birth when oxygen is readily available. To continue this investigation, I propose two aims 1) to determine whether VHL mediates a switch between glycolysis and mitochondrial respiration to signal nephron progenitor differentiation and 2) to define the interactions between VHL and mitochondria in nephron progenitor fate decisions. These findings will demonstrate the necessity of strict developmental VHL regulation and serve to identify novel therapeutic targets for kidney disease treatment. !