Cellular mechanobiology and engineering of active brown adipose tissue

活性棕色脂肪组织的细胞力学生物学和工程

• 批准号: 10170330
• 负责人: Sanjay Kumar
• 金额: $ 56.94万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170330
• 关键词: Actomyosin; Acute; Address; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Animals; Biochemical; Biocompatible Materials; Body Weight decreased; Brown Fat; Burn injury; Calcium Channel; Calories; Cell Respiration; Cells; Contractile System; Country; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Disease; Dissection; Engineering; Event; Extracellular Matrix; Fatty acid glycerol esters; Gene Expression; Generations; Genetic Models; Genetic Transcription; Goals; In Vitro; Integrins; Isoproterenol; Lead; Link; MYLK gene; Measurement; Measures; Mechanical Stimulation; Mechanics; Mesenchymal Stem Cells; Metabolic; Microscopy; Mitochondrial Proteins; Modeling; Molecular; Muscle; Myosin ATPase; Myosin Light Chain Kinase; Myosin Type II; Non-Insulin-Dependent Diabetes Mellitus; Nonmuscle Myosin Type IIA; Obesity; Obesity Epidemic; Output; Pathway interactions; Periodicity; Proteins; Public Health; Relaxation; Role; Signal Transduction; Stretching; Structure; System; Talin; Technology; Testing; Thermogenesis; Tissue Differentiation; Tissues; Translations; Work; base; cofactor; combat; design; energy balance; fighting; in vivo; inducible gene expression; innovation; interest; lipid biosynthesis; mouse genetics; mutant; new technology; novel; overexpression; programs; response

PROJECT SUMMARY/ABSTRACT There is a dire need for new technologies to address the obesity epidemic and its associated sequellae, including Type II Diabetes. Increasing caloric output through expansion and activation of brown adipose tissue (BAT), which “burns” metabolic fuels to produce heat, is garnering increasing interest as a novel mechanism to trigger weight loss in adults. However, the technological translation of this approach, including the engineering of biomaterial platforms to support BAT in vitro and in vivo, has been limited by a poor understanding of how cues from the physical microenvironment regulate BAT activation. Our preliminary data hint at a novel and unexpected model in which beta-adrenergic (ß-AR) stimulation triggers BAT activation through a myosin- and YAP/TAZ-dependent mechanotransductive signaling network, ultimately enhancing expression of the heat- generating mitochondrial protein UCP1. This model has profound implications, because it would suggest that incorporation of mechanical cues within the microenvironment could be leveraged to activate BAT and promote caloric output as a strategy to combat obesity. Thus, the goal of this proposal is to critically test the hypothesis that ß-AR and mechanotransductive signaling collude to stimulate BAT activation and enhanced cellular respiration. We have three aims: (1) To dissect the mechanisms through which actomyosin tension acutely activates BAT; (2) To determine how mechanical activation of YAP/TAZ regulates expression of UCP1; and (3) To investigate the role of mechanosensitive YAP/TAZ-dependent signals in white/beige adipose fate determination. In addition to detailed dissection of signaling events, our approach features an innovative combination of engineered materials, mechanical stimulation, advanced mouse genetic models, inducible expression of myosin-activating proteins, and measurements of cell and tissue mechanics. Successful completion of this work would substantially advance our mechanistic understanding of BAT activation while informing the design of materials technologies to stimulate BAT activation to reduce obesity.

项目概要/摘要 迫切需要新技术来解决肥胖流行及其相关后遗症， 包括 II 型糖尿病，通过扩张和激活棕色脂肪组织来增加热量输出。 （BAT），它“燃烧”代谢燃料来产生热量，作为一种新机制引起了越来越多的兴趣 然而，这种方法的技术转化，包括工程设计。 体外和体内支持 BAT 的生物材料平台的开发受到了限制，因为对如何 来自物理微环境的线索调节 BAT 激活。 意想不到的模型，其中 β-肾上腺素能 (ß-AR) 刺激通过肌球蛋白和肌球蛋白触发 BAT 激活 YAP/TAZ 依赖的机械传导信号网络，最终增强热表达 生成线粒体蛋白 UCP1 该模型具有深远的意义，因为它表明 可以利用微环境中的机械线索来激活 BAT 并促进热量输出作为对抗肥胖的策略因此，该提案的目标是严格控制。 检验 ß-AR 和机械传导信号协同刺激 BAT 激活的假设 我们有三个目标：（1）剖析肌动球蛋白的机制。 张力急性激活BAT；（2）确定YAP/TAZ的机械激活如何调节表达 UCP1；和（3）研究机械敏感 YAP/TAZ 依赖性信号在白色/米色中的作用 除了信号事件的详细剖析之外，我们的方法还具有以下特点： 工程材料、机械刺激、先进的小鼠遗传模型的创新组合， 肌球蛋白激活蛋白的诱导表达以及细胞和组织力学的测量。 这项工作的成功完成将大大提高我们对 BAT 的机械理解 激活，同时为材料技术的设计提供信息，以刺激 BAT 激活以减少肥胖。