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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要在美国和其他地区，肥胖和超重健康压力的发生率有所上升过去 50 年里，与年龄相关的健康疾病（包括心血管疾病）的风险显着增加疾病、癌症和阿尔茨海默病的基础生物学的全面了解。驱动脂质储存和脂质动员的机制是应对这一挑战的关键部分。秀丽隐杆线虫已成为一个强大的模型系统，可用于识别机制我们将 TGFβ/BMP 信号传导确定为此类机制之一。 TGFβ/BMP 相关配体 DBL-1，发现 DBL-1/BMP 是正常脂质积累所必需的 DBL-1/BMP 部分通过下调胰岛素/IGF-1 样信号传导 (IIS) 来促进脂质储存。由 DAF-2 胰岛素受体和 DAF-16 FoxO 转录因子此外，DBL-1/BMP 介导。信号传导调节秀丽隐杆线虫阿尔茨海默病模型的结果，这可能与其相关我们现在寻求确定串扰及其下游的机制。使用多组学方法研究衰老过程中脂质代谢中 BMP 和 IIS 的效应因子。 DBL-1/BMP 信号通过其 Smad 转录因子通过 DAF-16/FoxO 与 IIS 串扰调节脂质代谢、脂肪积累和成人生理机能为了检验这一假设，我们将解决这一问题。具体目标如下：（1）确定介导BMP和IIS调控的转录网络 (2) 确定 DBL-1/BMP 如何影响 DAF-16/FoxO 基因组占用 (3) 确定由 DBL-1/BMP 和 IIS 活性决定的代谢特征。这些实验使用下一代组学方法，共同描述了完整的特征由 BMP 和 IIS 信号传导（及其交叉调节）指导的转录和脂质动态图衰老过程中完整有机体中的相互作用）这种使用秀丽隐杆线虫的方法和领域的整合。该模型不容易应用于其他系统，特别是在整个生物体衰老的背景下。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，我们期望对这些信号通路有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贡献包括代谢综合征和阿尔茨海默病。