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，肥胖和超重的发生率已经上升， 在过去的50年里， 疾病、癌症和阿尔茨海默病。全面了解潜在的生物学 驱动脂质储存和脂质动员的机制是应对这一挑战的关键。的 线虫秀丽隐杆线虫已成为一个强大的模式系统，其中确定机制 脂质体内平衡。我们确定TGFβ/BMP信号传导为这样的机制之一。我们专注于 TGFβ/BMP相关配体DBL-1，发现DBL-1/BMP是正常的脂质积累所必需的。 动物DBL-1/BMP通过下调胰岛素/IGF-1样信号（IIS）促进脂质储存， 是由β 2胰岛素受体和β 16 FoxO转录因子介导的。此外，DBL-1/BMP 信号调节C.阿尔茨海默氏症的秀丽线虫模型，这可能与其 在脂质代谢中起作用。我们现在寻求识别串扰的机制和下游信号。 BMP和IIS在衰老过程中脂质代谢的效应物，使用多Omic方法。我们假设 DBL-1/BMP信号通过其Smad转录因子与IIS通过p16/FoxO交叉作用， 调节脂质代谢、脂肪积累和成人生理。为了验证这一假设，我们将讨论 具体目的如下：（1）确定BMP和IIS调控的转录网络 脂质代谢;（2）确定DBL-1/BMP如何影响β-16/FoxO基因组占有率 信号传导;和（3）确定由DBL-1/BMP和IIS活性决定的代谢谱。采取 总之，这些实验，使用下一代组学方法，将表征完整的 由BMP和IIS信号传导（及其交叉调节）指导的转录和脂质动力学图 相互作用）。这种方法和领域的集成使用C。elegans 该模型不容易应用于其他系统，特别是在整个有机体老化的背景下。这些研究 还将生成未来假设驱动研究所需的详细转录组和代谢组。 由于这些信号通路的高度保守性，我们期待对以下方面有价值的见解： 调节脂质稳态的普遍机制原理及其对年龄相关疾病的作用 包括代谢综合征和阿尔茨海默病。

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.