Multi-Omic Analysis of BMP-Insulin Signaling Crosstalk in Lipid Metabolism during Aging

项目摘要 在美国和其他地方，肥胖和超重健康压力的发生率有所上升 在过去的50年里急剧增加了与年龄相关的健康疾病的风险，包括心血管疾病 疾病、癌症和阿尔茨海默氏症。全面了解潜在的生物学 驱动脂质储存和动员的机制是面对这一挑战的关键部分。这个 线虫秀丽线虫已经成为一种识别机制的强大模式系统 脂类动态平衡。我们发现转化生长因子β/骨形态发生蛋白信号转导机制之一。我们把重点放在 转化生长因子β/骨形态发生蛋白相关配体DBL-1发现，DBL-1/骨形态发生蛋白是正常脂肪堆积所必需的。 动物。DBL-1/BMP促进脂质储存部分是通过下调胰岛素/IGF-1样信号(IIS)，从而 是由DAF-2胰岛素受体和DAF-16FoxO转录因子介导的。此外，DBL-1/BMP 信号调节线虫阿尔茨海默病模型的结果，这可能与其 在脂类代谢中的作用。我们现在试图确定串扰和下行信号的机制 用多组学方法研究BMP和IIS在衰老过程中的脂代谢效应。我们假设 DBL-1/BMP信号通过其Smad转录因子通过DAF-16/FoxO与IIS串扰 调节脂肪代谢、脂肪堆积和成人生理。为了检验这一假设，我们将解决 具体目的如下：(1)确定介导BMP和IIS调控的转录网络。 脂代谢；(2)确定DBL-1/BMP对DAF-16/FoxO基因组占有率的影响 以及(3)确定由DBL-1/BMP和IIS活性决定的代谢谱。已被占用 总而言之，这些实验，使用下一代Omics方法，将表征完整的 BMP和IIS信号引导的转录和脂质动力学图(以及它们的交叉调节 相互作用)在一个完整的有机体中。这种使用线虫的方法和领域的整合 模型不容易应用于其他系统，特别是在整个生物体老化的背景下。这些研究 还将产生未来假说驱动研究所需的详细转录本和代谢体。 由于这些信号通路的高度保守，我们期待有价值的洞察 调节脂质稳态的普遍机制原理及其在老年性疾病中的作用 包括代谢综合征和阿尔茨海默氏症。

Project Summary The incidence of obesity and overweight health stress in the United States and elsewhere has elevated dramatically in the last 50 years, increasing the risk of age-related health disorders including cardiovascular disease, cancer, and Alzheimer’s disease. A comprehensive understanding of the underlying biological mechanisms that drive lipid storage and lipid mobilization is a critical piece in facing this challenge. The nematode Caenorhabditis elegans has emerged as a powerful model system in which to identify mechanisms of lipid homeostasis. We identified TGFβ/BMP signaling as one such mechanism. We focused on the TGFβ/BMP-related ligand DBL-1, discovering that DBL-1/BMP is required for normal lipid accumulation in the animal. DBL-1/BMP promotes lipid storage in part by downregulation of insulin/IGF-1-like signaling (IIS), which is mediated by the DAF-2 insulin receptor and the DAF-16 FoxO transcription factor. Moreover, DBL-1/BMP signaling modulates outcomes in a C. elegans model of Alzheimer’s disease, which may be related to its functions in lipid metabolism. We now seek to identify the mechanisms of crosstalk and the downstream effectors of BMP and IIS in lipid metabolism during aging using a multi-Omic approach. We hypothesize that DBL-1/BMP signaling through its Smad transcription factors crosstalks with IIS via DAF-16/FoxO to regulate lipid metabolism, fat accumulation, and adult physiology. To test this hypothesis, we will address the following specific aims: (1) Determine the transcriptional network mediating BMP and IIS regulation of lipid metabolism; (2) Identify how DAF-16/FoxO genome occupancy is influenced by DBL-1/BMP signaling; and (3) Determine the metabolic profiles dictated by DBL-1/BMP and IIS activity. Taken together, these experiments, using next-generation Omics methodologies, will characterize the complete picture of transcriptional and lipid dynamics directed by BMP and IIS signaling (and their cross-regulatory interaction) in an intact organism during aging. This integration of approaches and fields using the C. elegans model is not easily applied in other systems, particularly in the context of whole-organism aging. These studies will also generate detailed transcriptomes and metabolomes needed for future hypothesis-driven research. Due to the high degree of conservation of these signaling pathways, we anticipate valuable insight into universal mechanistic principles regulating lipid homeostasis and its contribution to age-related illnesses including metabolic syndrome and Alzheimer’s disease.