Gap Junction Dependent and Independent Roles of Connexin43 in Metabolic Tissues

项目概要/摘要本提案概述了朱毅博士的综合培训和研究计划， 在Philipp E博士的指导下完成进一步的学术培训。谢勒和过渡到 专门从事代谢中连接蛋白43（Cx43）生物学研究领域的独立研究者 适应研究建议的总体目标是了解多方面的作用， 间隙连接蛋白43对禁食期间肝脏FGF 21分泌的调节及其在脂肪组织中的作用 冷暴露期间的“beiging”。肥胖和糖尿病仍然是我们社会的巨大负担， 治疗肥胖症和糖尿病的药物未能达到治疗目标。因此，重要的是发现 新的途径可以用来对抗肥胖和糖尿病。最近，我发现Cx43 通道参与了脂肪组织中冷暴露引起的交感神经元输出的传播 组织.几种代谢组织中的系统性Cx43过表达改善了葡萄糖耐量， 小鼠的循环FGF 21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。所以我生成了几条新的鼠标线，以进一步研究 Connexin 43和FGF 21，关注Connexin 43在肝脏和脂肪组织中的代谢后果， 体内：目的1研究间隙连接蛋白43通道在胰高血糖素刺激的肝FGF 21中的作用。 同时探讨Connexin 43调控FGF 21表达的机制。 目的2：追踪一个新的观察结果，即在脂肪细胞增殖过程中，连接蛋白43易位到米色脂肪细胞线粒体中。 冷暴露，并测试假设，线粒体易位Cx43介导的UCP 1非依赖性 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连接蛋白43的了解， 脂肪组织，并指导我们在靶向Cx43的代谢疾病，在通道， 半通道，或者简单地说是转录水平。在德克萨斯大学西南分校的赞助下， 医疗中心，我将由国际公认的领导人在新陈代谢领域，这将有助于指导 我的研究生涯向独立调查员的转变。

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.