Mechanisms of Wnt Signaling in Regulating Metabolism and Mammalian Aging

Wnt 信号传导调节代谢和哺乳动物衰老的机制

• 批准号: 8308468
• 负责人: Hongjun Liu
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308468
• 关键词: Adult; Aging; Animal Model; Back; Belief; Binding; Biological Process; Blood Circulation; Caenorhabditis elegans; Cell Communication; Cell physiology; Cells; Chronic; Complex; DNA; Diabetes Mellitus; Diet; Down-Regulation; Embryonic Development; Endocrine; Energy Metabolism; Family; Fatty acid glycerol esters; Feedback; Genetic; Genetic Models; Goals; Homeostasis; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Knock-out; Life; Longevity; Lower Organism; Maintenance; Mammals; Membrane; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Mutation; Obesity; Organ; Pathway interactions; Peripheral; Phosphorylation; Phosphorylation Inhibition; Pituitary Gland; Play; Proliferating; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Reporter; Reporting; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Signaling Molecule; Stem cells; Stress; Testing; Tissues; Transgenic Mice; Up-Regulation; Yeasts; adult stem cell; blood glucose regulation; body system; db/db mouse; diabetic; feeding; gain of function; gain of function mutation; glucose metabolism; in vivo; inhibitor/antagonist; insight; insulin sensitivity; insulin signaling; lipoprotein receptor-related protein 6; loss of function; loss of function mutation; mouse model; mutant; novel; receptor; regenerative; self-renewal; senescence; stem cell niche

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 ofthe 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 rnay 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.

这项研究的主要目标是研究 Wnt 信号如何调节哺乳动物衰老。 Wnt 是一个分泌蛋白家族，在胚胎发生和发育过程中的细胞间通讯中发挥着重要作用。 用于维持成体干细胞生态位和整体组织/器官稳态。我们最近报道称 哺乳动物衰老调节因子 klotho 作为分泌型 Wnt 拮抗剂，在缺乏 klotho 的情况下，在体内 Wnt 信号传导增强。我们进一步观察到 Wnt 信号的长期上调有助于 多个组织内增殖祖细胞的加速衰老和干细胞的消耗 和克洛索缺陷小鼠的器官。这些结果表明 Wnt 信号传导可能发挥重要作用 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 信号传导在调节多种物种的衰老过程中发挥着重要作用，我们推测 Wnt 和胰岛素途径的交叉可能在衰老的整体调节中发挥重要作用。相似地， 因为 Wnt 信号传导对于干细胞自我更新和组织/器官维护至关重要，并且因为胰岛素 作为能量代谢的主要调节者，我们相信这些观察结果可能提供 新陈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的代谢模型和遗传模型来检验这一假设 失调。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。我们还将研究分子机制 胰岛素通过何种途径抑制 Wnt 信号传导，以及 Wnt 信号传导如何反馈调节血糖 代谢。总的来说，这项研究从两种新的角度研究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叉以及Wnt如何 信号传导和胰岛素信号传导可能在调节衰老方面交叉。我们相信这项研究将提供 为我们理解代谢调节及其潜在机制提供了新的见解 哺乳动物的衰老。

项目成果

Wnt signaling regulates hepatic metabolism.

• DOI: 10.1126/scisignal.2001249
• 发表时间: 2011-02-01
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Liu H;Fergusson MM;Wu JJ;Rovira II;Liu J;Gavrilova O;Lu T;Bao J;Han D;Sack MN;Finkel T
• 通讯作者: Finkel T

Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy.

• DOI: 10.18632/aging.100038
• 发表时间: 2009-04-09
• 期刊: Aging
• 作者: Wu JJ;Quijano C;Chen E;Liu H;Cao L;Fergusson MM;Rovira II;Gutkind S;Daniels MP;Komatsu M;Finkel T
• 通讯作者: Finkel T

Bmi1 regulates mitochondrial function and the DNA damage response pathway.

• DOI: 10.1038/nature08040
• 发表时间: 2009-05-21
• 期刊: Nature
• 影响因子: 64.8
• 作者: Liu J;Cao L;Chen J;Song S;Lee IH;Quijano C;Liu H;Keyvanfar K;Chen H;Cao LY;Ahn BH;Kumar NG;Rovira II;Xu XL;van Lohuizen M;Motoyama N;Deng CX;Finkel T
• 通讯作者: Finkel T