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

衰老过程中脂质代谢中 BMP-胰岛素信号串扰的多组学分析

• 批准号: 10553134
• 负责人: Christopher G Rongo
• 金额: $ 19.97万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553134
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; BMP2 gene; Binding; Biochemical; Bioinformatics; Biological; Biological Models; Bone Morphogenetic Proteins; CRISPR/Cas technology; Caenorhabditis elegans; Cardiovascular Diseases; Cells; ChIP-seq; Data; Disease; Down-Regulation; Dyslipidemias; Enzymes; Fatty Acid Desaturases; Fatty acid glycerol esters; Fostering; Foundations; Future; Gene Expression Regulation; Genetic Transcription; Genome; Genomics; Health; Homeostasis; Hyperglycemia; Hypertension; Incidence; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Ligands; Lipid Mobilization; Lipids; Longevity; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Methodology; Modeling; Nematoda; Neurodegenerative Disorders; Obesity; Organism; Orthologous Gene; Outcome; Overweight; Pathway interactions; Physiological; Physiology; Population; Public Health; Regulation; Regulatory Pathway; Research; Risk; Risk Factors; Signal Pathway; Signal Repression; Signal Transduction; Signaling Protein; Specificity; Stress; System; Technology; Testing; Tissues; Transducers; Transforming Growth Factor beta; United States; Whole Organism; age related; aged; cardiovascular disorder risk; cofactor; experimental study; genome-wide analysis; healthspan; in vivo; insight; insulin regulation; insulin signaling; insulin-like peptide; lipid metabolism; lipidomics; metabolic profile; metabolome; metabolomics; model organism; multiple omics; mutant; next generation; oxidation; procollagen C-endopeptidase; programs; reproductive; transcription factor; transcriptome; transcriptome sequencing

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.

项目摘要 美国和其他地方的肥胖和超重健康压力事件已升高 在过去的50年中，急剧增加了与年龄相关的健康障碍（包括心血管）的风险 疾病，癌症和阿尔茨海默氏病。对基本生物学的全面理解 驱动脂质存储和脂质动员的机制对于面对这一挑战是至关重要的。这 线虫秀丽隐杆线虫已成为一种强大的模型系统，以识别机制 脂质稳态。我们将TGFβ/BMP信号识别为这样的机制。我们专注于 TGFβ/BMP相关的配体DBL-1，发现在正常脂质积累中需要DBL-1/BMP 动物。 DBL-1/BMP通过下调胰岛素/IGF-1样信号（IIS）来促进脂质存储 由DAF-2胰岛素受体和DAF-16 FOXO转录因子介导。此外，DBL-1/BMP 在阿尔茨海默氏病的秀丽隐杆线虫模型中的信号调制结果，这可能与其 脂质代谢的功能。我们现在寻求确定串扰和下游的机制 BMP和IIS在衰老过程中使用多摩变方法在脂质代谢中的影响。我们假设这一点 DBL-1/BMP通过其SMAD转录因子与IIS通过DAF-16/FOXO串扰的信号传导 调节脂质代谢，脂肪积累和成人生理学。为了检验这一假设，我们将解决 以下具体目的：（1）确定介导BMP和IIS调节的转录网络 脂质代谢； （2）确定DAF-16/FOXO基因组占用率如何受到DBL-1/BMP的影响 信号传导； （3）确定由DBL-1/BMP和IIS活性决定的代谢谱。拍摄 共同使用下一代法方法的这些实验将表征完整 BMP和IIS信号传导指导的转录和脂质动力学的图片（及其交叉调节 衰老过程中完整生物的相互作用）。使用秀丽隐杆线虫的这种方法和田野的整合 模型不容易应用于其他系统，尤其是在全生物衰老的背景下。这些研究 还将生成未来假设驱动的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护，我们预计 普遍的机械原理调节脂质稳态及其对年龄相关疾病的贡献 包括代谢综合征和阿尔茨海默氏病。