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 该提案概述了朱毅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 专门从事 Connexin43 (Cx43) 代谢生物学研究领域的独立研究者 适应。该研究计划的总体目标是了解 Connexin43对禁食期间肝脏FGF21分泌的调节及其在脂肪组织中的作用 冷暴露时呈“米色”。肥胖和糖尿病仍然是我们社会的巨大负担，当前 治疗肥胖和糖尿病的药物尚未达到治疗目标。所以发现很重要 可用于对抗肥胖和糖尿病的新途径。最近，我发现CX43 通道与脂肪中冷暴露引起的交感神经元输出的传播有关 组织。多个代谢组织中的系统性 Cx43 过度表达可改善葡萄糖耐量并提高血糖水平 小鼠循环 FGF21 水平，这是一种具有多效代谢作用的激素，具有巨大的潜力 发展成为药物。所以我生成了几条新的鼠标线来进一步研究之间的串扰 Connexin43 和 FGF21，重点关注 Connexin43 在肝脏和脂肪组织中的代谢后果 体内：目标 1 研究 Connexin43 间隙连接通道在胰高血糖素刺激的肝脏 FGF21 中的作用 空腹期间的分泌，并探讨Connexin43调节FGF21表达的机制。 目标 2 跟进了一项新观察，即 Connexin43 在 冷暴露，并检验线粒体易位 Cx43 介导 UCP1 独立的假设 在米色脂肪细胞中解偶联。这些拟议的研究将扩展我们对肝脏和肝脏中 Connexin43 的了解。 脂肪组织，并指导我们在药理学上靶向 Cx43 治疗代谢性疾病 半通道，或简称转录水平。在德克萨斯大学西南分校的赞助下 医疗中心，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研究者职位的转变。