Gap Junction Dependent and Independent Roles of Connexin43 in Metabolic Tissues

Connexin43 在代谢组织中的间隙连接依赖性和独立作用

• 批准号: 10056398
• 负责人: Yi Zhu
• 金额: $ 24.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056398
• 关键词: Academic Training; Acclimatization; Acute; Adipocytes; Adipose tissue; Affect; Binding; Biology; Blood Glucose; Cardiac Myocytes; Cell membrane; Cells; Cellular Metabolic Process; Connexin 43; Connexins; Coupling; Data; Dependovirus; Diabetes Mellitus; Dyes; Evolution; Exposure to; Fasting; Gap Junctions; Genes; Genetic Transcription; Glucagon; Goals; Hepatic; Hepatocyte; High Fat Diet; Hormones; International; Knowledge; Life; Liver; Mass Spectrum Analysis; Measures; Mediating; Medical center; Medicine; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Mus; Neurons; Obesity; Organ; Organism; Output; Oxygen Consumption; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacology; Physiology; Positioning Attribute; Proteins; Proteomics; Protons; Publishing; Regulation; Research; Research Personnel; Research Proposals; Respiration; Role; Signal Pathway; Signal Transduction; Societies; Subcellular Fractions; Testing; Texas; Tissues; Training; Transcript; Universities; adipocyte differentiation; blood glucose regulation; career; clinical development; combat; experimental study; feeding; fibroblast growth factor 21; gap junction channel; glucose tolerance; improved; in vivo; insight; luciferin; novel; novel therapeutics; overexpression; response

Project Summary/Abstract This proposal outlines an integrated training and research plan for Dr. Yi Zhu to complete further academic training under the mentorship of Dr. Philipp E. Scherer and transition to an independent investigator specializing in the research field of Connexin43 (Cx43) biology in metabolic adaptation. The overall objective of the research proposal is to understand the multifaceted roles of Connexin43 in the regulation of hepatic FGF21 secretion during fasting as well as its role in adipose tissue “beiging” during cold exposure. Obesity and diabetes remain a great burden to our society, and current medicines for obesity and diabetes have fell short of achieving treatment goals. So it is important to discover novel pathways that can be leveraged in combating obesity and diabetes. Recently, I have identified that Cx43 channels are implicated in the propagation of sympathetic neuronal outputs from cold exposure in adipose tissue. Systemic Cx43 overexpression in several metabolic tissues improves glucose tolerance and elevates circulating FGF21 levels in mice, a hormone with pleiotropic metabolic actions and holds great potential to be developed into a medication. So I generated several new mouse lines to further study the crosstalk between Connexin43 and FGF21, focusing on metabolic consequences of Connexin43 in liver and adipose tissues in vivo: Aim 1 investigates the role of Connexin43 gap junction channel in glucagon-stimulated hepatic FGF21 secretion during fasting, and also explore the mechanism by which Connexin43 regulates FGF21 expression. Aim 2 follows up on a new observation that Connexin43 translocates into beige adipocyte mitochondria during cold exposure, and tests the hypothesis that mitochondrial translocated Cx43 mediates UCP1-independent uncoupling in beige adipocytes. These proposed studies will expand our knowledge on Connexin43 in liver and adipose tissue, and guide us in pharmacologically targeting Cx43 for metabolic diseases, at the channel, the hemichannel, or simply the transcription levels. Under the auspices of the University of Texas Southwestern Medical Center, I will be mentored by internationally recognized leaders in the metabolism field, which will aid the transition of my research career toward an independent investigator position.

项目摘要/摘要本建议概述了一项针对伊朱博士的综合培训和研究计划 在Philipp E.Scherer博士的指导下完成进一步的学术培训，并过渡到 独立研究员，专门从事连接蛋白43(Cx43)代谢生物学的研究领域 适应。研究提案的总体目标是了解 缝隙连接蛋白43对禁食时肝脏FGF21分泌的调节及其在脂肪组织中的作用 在寒冷的暴露中“褐变”。肥胖和糖尿病仍然是我们社会的一个巨大负担，目前 治疗肥胖症和糖尿病的药物一直没有达到治疗目标。所以重要的是要发现 可用于抗击肥胖和糖尿病的新途径。最近，我发现Cx43 经络与冷暴露于脂肪的交感神经元输出的传播有关 组织。系统性Cx43在几种代谢组织中的过表达改善糖耐量并提高 小鼠循环中FGF21水平，一种具有多效性代谢作用的激素，具有很大的潜力 发展成为一种药物。所以我产生了几个新的鼠标线来进一步研究 Cx43和FGF21，侧重于Cx43在小鼠肝脏和脂肪组织中的代谢影响 体内：目的1研究间隙连接蛋白43在胰高血糖素刺激的肝脏成纤维细胞生长因子21中的作用 此外，还探讨了连接蛋白43调节FGF21表达的机制。 目的2跟进一项新的观察，即连接蛋白43移位到米色脂肪细胞线粒体中 冷暴露，并检验线粒体易位Cx43介导UCP1非依赖性的假设 米色脂肪细胞解偶联。这些拟议的研究将扩大我们对肝脏和肝脏中连接蛋白43的了解 脂肪组织，并指导我们在药物上靶向Cx43治疗代谢性疾病，在经络， 半通道，或简单地说转录水平。由德克萨斯大学西南分校赞助 医学中心，我将得到新陈代谢领域国际公认的领导者的指导，这将有助于 我的研究生涯向独立调查员职位的转变。