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

基本信息

批准号：
9912145
负责人：
Sanjay Kumar
金额：
$ 57.09万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
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/9912145
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

项目摘要

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.