Mechanisms of Wnt Signaling in Regulating Metabolism and Mammalian Aging

这项拟议研究的广泛目标是研究Wnt信号如何调节哺乳动物衰老。 Wnt是一个分泌蛋白家族，其在胚胎发生期间的细胞间通讯中很重要， 用于维持成体干细胞小生境和整体组织/器官稳态。我们最近报道说， 哺乳动物衰老调节剂klotho充当分泌的Wnt拮抗剂，并且在不存在klotho的情况下，在体内 Wnt信号增强。我们进一步观察到，Wnt信号的慢性上调有助于细胞凋亡。 加速增殖祖细胞的衰老和多种组织内干细胞的耗竭 和klotho缺陷小鼠的器官。这些结果表明，Wnt信号可能发挥重要作用， 调节哺乳动物衰老的作用。我们最近进一步探索了其他潜在的内源性调节因子 并发现胰岛素刺激可以强烈抑制Wnt信号传导。由于胰岛素 信号在调节大范围物种的衰老中起着重要作用，我们推测， Wnt和胰岛素途径的交叉在衰老的整体调节中可能是重要的。同样地， 由于Wnt信号传导对于干细胞自我更新和组织/器官维持是必需的， 作为能量代谢的主要调节器，我们相信这些观察可能会提供一个 代谢可能直接影响组织维持并最终影响哺乳动物衰老的机制。在 在这项拟议的研究中，我们将使用饮食诱导和遗传代谢模型来验证这一假设。 紊乱我们将研究肥胖及其相关的高循环胰岛素浓度对 成体干细胞的自我更新能力和整体功能。我们还将研究 胰岛素抑制Wnt信号的机制，以及Wnt信号如何反馈调节葡萄糖 新陈代谢.总的来说，这项研究从两个新的方面探讨了哺乳动物衰老的机制。 观点：能量代谢如何与干细胞功能和器官稳态相交，以及Wnt如何与干细胞相互作用。 信号传导和胰岛素信号传导可能在调节衰老中交叉。我们相信这项研究将提供 新的见解，在我们的理解代谢调节以及对机制的基础上， 哺乳动物衰老

The broad goal of this proposed research is to investigate how Wnt signaling regulates mammalian aging. Wnt's are a family of secreted proteins that are important in cell-cell communication during embryogenesis and for maintaining adult stem cell niches and overall tissue/organ homeostasis. We recently reported that the mammalian aging regulator klotho acts as a secreted Wnt antagonist and that in the absence of klotho, in vivo Wnt signaling is augmented. We further observed that chronic up-regulation of Wnt signaling contributes to the accelerated senescence of proliferating progenitor cells and the depletion of stem cells within multiple tissues and organs of the klotho deficient mouse. These results suggest that Wnt signaling might play an important role in regulating mammalian aging. We have recently further explored other potential endogenous regulators of Wnt signaling and have discovered that insulin stimulation can strongly inhibit Wnt signaling. Since insulin signaling plays an important role in regulating aging in a wide range of species, we speculate that the intersection of the Wnt and insulin pathways may be important in the overall regulation of aging. Similarly, since Wnt signaling is essential for stem cell self renewal and tissue/organ maintenance and since insulin functions as a major regulator of energy metabolism, we believe these observations might provide a mechanism by which metabolism might directly impact tissue maintenance and ultimately mammalian aging. In this proposed study, we will test this hypothesis using both diet-induced and genetic models of metabolic disorders. We will investigate the effects of obesity and its associated high circulating insulin concentrations on adult stem cell self renewal capacity and overall function. We will also investigate the molecular mechanisms by which insulin inhibits Wnt signaling, as well as how Wnt signaling may feedback to regulate glucose metabolism. Overall this proposed study investigates the mechanisms of mammalian aging from two novel view points: How energy metabolism intersects with stem cell function and organ homeostasis and how Wnt signaling and insulin signaling might intersect in regulating aging. It is our belief that this study will provide novel insights in our understanding of both metabolic regulation as well as on the mechanisms underlying mammalian aging.