Mechanisms of Wnt Signaling in Regulating Metabolism and Mammalian Aging

这项拟议的研究的主要目标是调查Wnt信号如何调节哺乳动物的衰老。 WNT是一个分泌蛋白家族，在胚胎发育和细胞间的交流中起重要作用。 用来维持成体干细胞的位置和整体组织/器官的动态平衡。我们最近报道说， 哺乳动物衰老调节剂Klotho在体内作为一种分泌的Wnt拮抗剂，在没有Klotho的情况下 增强了WNT信令。我们进一步观察到，Wnt信号的慢性上调有助于 增殖中的祖细胞加速衰老和多组织内干细胞的枯竭 以及Klotho缺陷小鼠的器官。这些结果表明Wnt信号可能起着重要的作用 在调节哺乳动物衰老方面的作用。我们最近进一步探索了其他潜在的内源性调节因子 并发现胰岛素刺激能强烈抑制Wnt信号转导。自胰岛素以来 信号在调节多种物种的衰老方面起着重要作用，我们推测 Wnt和胰岛素通路的交集在衰老的整体调控中可能是重要的。同样， 由于Wnt信号对干细胞自我更新和组织/器官维持是必不可少的，而且由于胰岛素 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……里面 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 精神错乱。我们将研究肥胖及其相关的高循环胰岛素浓度对 成体干细胞自我更新能力和整体功能。我们还将研究其分子机制。 胰岛素通过哪些途径抑制Wnt信号，以及Wnt信号如何反馈调节血糖 新陈代谢。总体而言，这项拟议的研究从两个新的角度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动态平衡相交 信号转导和胰岛素信号转导可能在调节衰老方面有交叉作用。我们相信，这项研究将提供 在我们对代谢调节以及潜在机制的理解中的新见解 哺乳动物的衰老。

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.