Life span, Fat Storage and Insulin-like Signaling

描述(申请人提供)：在哺乳动物中，胰岛素信号、寿命和脂肪储存之间似乎有密切的联系。胰岛素信号的减少会促进过多的脂肪储存，而肥胖会导致胰岛素不敏感。我们使用线虫来解释我们的假设，包括转化生长因子-2和TOR在内的多种保守的信号通路调节胰岛素/IGF-1信号，以协调调节寿命和脂肪储存。线虫拥有一条胰岛素/IGF-1信号通路，这种信号通路在不同物种之间是非常保守的。调节这一途径会导致寿命和脂肪储存的变化。因此，蠕虫是一个很好的系统，可以确定多种途径如何影响胰岛素/IGF-1信号通路的寿命和脂肪储存调节。为了解决我们的假设，我们将实现以下三个具体目标：(1)我们将剖析转化生长因子-2和胰岛素/IGF-1信号通路之间的串扰；(2)我们将剖析TOR和胰岛素/IGF-1信号之间的串扰；(3)我们将识别调节胰岛素/IGF-1信号通路以调节寿命和脂肪储存的磷酸酶。这些磷酸酶可能调节胰岛素/IGF-1信号通路，或与胰岛素/IGF-1信号通路耦合的多个保守通路之一。从长远来看，这些研究应该有助于理解与II型糖尿病等疾病相关的复杂性。 与公共健康相关：胰岛素/IGF-1信号通路在系统发育过程中是保守的。在这个方案中，我们剖析了额外的保守信号通路如何与胰岛素/IGF-1信号通路结合来协同调节寿命和脂肪储存。

DESCRIPTION (provided by applicant): In mammals, there appears to be an intimate linkage between insulin signaling, life span, and fat storage. Reductions in insulin signaling promote excess fat storage, and obesity can result in insulin insensitivity. We use the nematode C. elegans to address our hypothesis that multiple conserved signaling pathways including TGF-2 and TOR, modulate insulin/IGF-1 signaling to coordinately regulate life span and fat storage. C. elegans possess an insulin/IGF-1 signaling pathway that is well conserved across species. Modulating this pathway leads to changes in life span and fat storage. Therefore, worms are an excellent system to determine how multiple pathways influence the insulin/IGF-1 signaling pathway for life span and fat storage regulation. To address our hypothesis we will perform the following three specific aims (1) We will dissect the cross talk between the TGF-2 and insulin/IGF-1 pathways (2) We will dissect the cross talk the TOR and insulin/IGF-1 signaling (3) We will identify phosphatases that regulate the Insulin/IGF-1 signaling pathway to modulate life span and fat storage. These phosphatases may regulate the insulin/IGF-1 signaling pathway or one of the multiple conserved pathways that couple the insulin/IGF-1 pathway. Over the long term, these studies should help to understand the complexities associated with diseases such as Type II diabetes. PUBLIC HEALTH RELEVANCE: The insulin/IGF-1 signaling pathway is conserved across phylogeny. In this proposal, we dissect how additional conserved signaling pathways couple with the insulin/IGF-1 signaling pathway to cooperatively regulate life span and fat storage.