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: 10415961
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415961
• 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; mechanical signal; 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.

项目摘要/摘要 迫切需要新技术来解决肥胖流行病及其相关的后遗症， 包括II型糖尿病。通过棕色脂肪组织的扩张和激活来增加热量输出 “燃烧”新陈代谢燃料以产生热量的(BAT)作为一种新的机制正引起越来越多的兴趣 在成年人中引发减肥。然而，这种方法的技术翻译，包括工程 在体外和体内支持BAT的生物材料平台的研究一直受到限制，因为对如何 来自物理微环境的信号调节蝙蝠的激活。我们的初步数据暗示了一部小说和 意想不到的模型中，β-肾上腺素能(？AR)刺激通过肌球蛋白触发BAT激活 YAP/TAZ依赖的机械转导信号网络，最终增强热- 产生线粒体蛋白UCP1。这一模型具有深远的影响，因为它将表明 微环境中的机械线索的结合可以被用来激活BAT 并将促进卡路里输出作为对抗肥胖的一项战略。因此，这项提案的目标是批判性地 检验以下假设：？-AR和机械传导信号合谋刺激BAT激活和 细胞呼吸增强。我们有三个目标：(1)剖析肌动球蛋白 张力强烈激活BAT；(2)确定YAP/TAZ的机械激活如何调节表达 以及(3)研究机械敏感信号YAP/TAZ在白色/米色中的作用 脂肪命运的决定。除了对信令事件的详细分析外，我们的方法还具有 工程材料、机械刺激、先进的小鼠遗传模型、 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极大地促进我们对BAT的机械性理解 激活的同时通知材料技术的设计，以刺激蝙蝠的激活，以减少肥胖。