Unraveling the role of osteocytes in metabolic dysfunction associated with obesity

揭示骨细胞在肥胖相关代谢功能障碍中的作用

基本信息

批准号：
10618056
负责人：
Neha Dole
金额：
$ 14.09万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618056
关键词：
3-Dimensional ATAC-seq Ablation Affect Behavior Biochemical Cells ChIP-seq Chromatin Clinical Cues Data Diet Disease Dose Eating Energy Metabolism Epidemic Epigenetic Process Foundations Functional disorder Future Glycolysis Goals Health High Fat Diet Hormones Hyperglycemia Hyperlipidemia In Vitro Intervention Knowledge Link Mediating Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Mitochondria Modeling Molecular Monitor Mus Musculoskeletal Neurosecretory Systems Nutrient Nutritional Obesity Osteocytes Oxidative Phosphorylation Pathway interactions Pattern Pharmacology Phenotype Physiological Play Prevalence Regulation Research Role SIRT1 gene Serum Shapes Signal Transduction Skeleton Testing Therapeutic Thinness Time Tissues Transforming Growth Factor beta Transforming Growth Factor beta Receptors Weight Gain Work age related bone bone cell bone fragility diet-induced obesity energy balance epigenome glucose metabolism histone modification improved in vivo insight lipid metabolism metabolic abnormality assessment multiple omics novel outcome prediction programs response success trait transcriptome transcriptome sequencing

项目摘要

PROJECT ABSTRACT The prevalence of obesity is on the rise and a better understanding of the drivers of this epidemic is crucial. As novel insights implicate bone in regulating energy metabolism, it is crucial to understand how diseases of positive energy balance, like obesity, affect the different functions of bone. While obesity is known to impact the structural function of bone causing increased fragility, it is unclear how the metabolic function of bone is compromised in obesity. Filling this gap in our knowledge is critical for developing therapeutics that can reestablish energy metabolism while maintaining musculoskeletal health in obesity. In this proposal, we explore the effects of obesity on bone regulated energy metabolism and focus particularly on osteocytes, that constitute 95% of cells in bone. Our compelling preliminary data puts forth the premise that TGFβ signaling is a key modulator of osteocyte-intrinsic energy metabolism (cellular). Thus, we test the hypothesis that obesity impacts osteocytic TGFβ signaling that in turn contributes to deregulated systemic energy metabolism. Furthermore, our data suggest that osteocytic TGFβ signaling also coordinates the activities of epigenetic factors to shape the transcriptome of osteocytes. These epigenetic factors have previously been implicated in obesity; however, their relation to TGFβ signaling and cellular energy metabolism of osteocytes remains unexplored. Together, these findings motivate my central hypothesis, that osteocytic TGFβ signaling drives metabolic dysfunction in obesity through an epigenetic mechanism. My aims to test this hypothesis are to: 1) determine if obesity induces metabolic reprogramming in osteocytes in a TGFβ- dependent manner, 2) determine if ablation of osteocytic TGFβ rescues metabolic dysfunction in obesity, and 3) identify the function of TGFβ responsive epigenetic factors in regulating osteocyte driven energy metabolism during obesity. Using hyperglycemia and hyperlipidemia (in vitro) and DIO (diet-induced obesity, in vivo) to model obesity, we will monitor the link between osteocytic TGFβ signaling, cellular- and systemic- energy metabolism, and study its role in regulating the obesity-induced metabolic dysfunction. For combining ChIP- Seq, ATAC-Seq, and RNA-Seq approaches, we will generate a network landscape connecting epigenetic marks, modifiers, chromatin accessibility patterns, and corresponding molecular pathways that are impacted by obesity in osteocytes. In the future, this landscape of molecular and epigenetic networks will serve as a blueprint that can be used to interpret osteocyte function in metabolism in response to distinct nutrient cues. Such a blueprint will be particularly informative in devising or predicting outcomes of pharmacologic interventions and will lay the foundation for my independent research that dissects the intricacies behind the crosstalk between bone function and energy metabolism. Project Abstract

项目摘要肥胖症的患病率正在上升，需要更好地了解这种流行病的驱动因素由于新的见解表明骨骼参与调节能量代谢，因此了解其机制至关重要。正能量平衡疾病，如肥胖，会影响骨骼的不同功能，而肥胖是众所周知的。影响骨骼的结构功能，导致脆性增加，目前尚不清楚骨骼的代谢功能如何肥胖导致骨骼受损，填补这一知识空白对于开发可治疗的疗法至关重要。重建能量代谢，同时保持肥胖患者的肌肉骨骼健康。在本提案中，我们探讨了肥胖对骨调节能量代谢的影响，并重点关注特别是骨细胞，它构成了骨骼中 95% 的细胞，我们令人信服的初步数据表明了这一点。前提是 TGFβ 信号传导是骨细胞内在能量代谢（细胞）的关键调节剂。检验肥胖影响骨细胞 TGFβ 信号转导进而导致失调的假设此外，我们的数据表明骨细胞 TGFβ 信号传导也能协调。表观遗传因子的活动塑造骨细胞的转录组。之前曾被认为与肥胖有关；然而，它们与 TGFβ 信号传导和细胞能量代谢的关系骨细胞的作用仍未被探索，这些发现激发了我的中心假设，即骨细胞。 TGFβ 信号传导通过表观遗传机制驱动肥胖的代谢功能障碍。假设是：1）确定肥胖是否会诱导 TGFβ- 中骨细胞的代谢重编程依赖的方式，2）确定骨细胞TGFβ的消融是否可以挽救代谢功能障碍肥胖，3) 确定 TGFβ 反应性表观遗传因子在调节骨细胞中的功能肥胖期间驱动能量代谢。使用高血糖和高脂血症（体外）和 DIO（饮食诱导的肥胖，体内）来建模肥胖，我们将监测骨细胞 TGFβ 信号传导、细胞能量和全身能量之间的联系代谢，并研究其在调节肥胖引起的代谢功能障碍中的作用。 Seq、ATAC-Seq 和 RNA-Seq 方法，我们将生成连接表观遗传的网络景观标记、修饰符、染色质可及性模式以及受其影响的相应分子途径未来，这种分子和表观遗传网络的景观将成为骨细胞的肥胖症。可用于解释骨细胞在代谢中响应不同营养线索的功能的蓝图。这样的蓝图对于设计或预测药理学结果将特别提供信息。干预措施，并将为我的独立研究奠定基础，剖析背后的复杂性骨功能和能量代谢之间的串扰。项目摘要