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/摘要本提案概述了Yi Zhu博士的集成培训和研究计划 在Philipp E. Scherer博士的心态下完成进一步的学术培训，并过渡到 独立研究者专门研究代谢中的Connexin43（CX43）生物学研究领域 适应。研究建议的总体目的是了解 在禁食过程中肝FGF21分泌的调节中的connexin43及其在脂肪组织中的作用 在冷曝光期间“存在”。肥胖和糖尿病仍然对我们的社会造成极大的燃烧，目前 肥胖和糖尿病的药物未能实现治疗目标。因此，发现很重要 可以利用肥胖和糖尿病来利用的新途径。最近，我确定了CX43 在脂肪中冷暴露的交感神经元输出传播中实现了渠道 组织。几种代谢组织中的全身性CX43过表达可提高葡萄糖耐受性并升高 在小鼠中循环FGF21水平，这是一种具有多效代谢作用的马，具有很大的潜力 发展成药物。因此，我生成了几种新的鼠标线，以进一步研究 Connexin43和FGF21，重点介绍肝脏中康纳克斯蛋白43的代谢后果和脂肪时机 Vivo：AIM 1研究了连接蛋白43间隙连接通道在胰高血糖素刺激的肝FGF21中的作用 禁食过程中的分泌，还探讨了连接蛋白43调节FGF21表达的机制。 AIM 2跟随了一个新的观察结果，即连接在 冷暴露，并检验了线粒体易位的CX43培养基UCP1无关的假设 在米色脂肪细胞中解偶联。这些拟议的研究将扩大我们对肝脏中connexin43的了解， 脂肪组织，并指导我们的药物靶向CX43，用于代谢性疾病，在该通道， 半通道或简单的转录水平。在德克萨斯大学西南大学的主持下 医疗中心，国际认可的新陈代谢领域将考虑我，这将有助于 我的研究职业向独立研究者职位的过渡。