CTRP and Metabolic Control

CTRP 和代谢控制

• 批准号: 9339679
• 负责人: Guang William Wong
• 金额: $ 48.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339679
• 关键词: Adipocytes; Adipose tissue; Antibodies; Antidiabetic Drugs; Biology; Blood; Budgets; Cardiovascular Diseases; Cell model; Clinical; Communication; Complement 1q; Coupled; Data; Diabetes Mellitus; Disease Outcome; Energy Metabolism; Family; Family member; Fatty Liver; GLUT 4 protein; GLUT4 gene; Genes; Genetic; Glucose; Goals; Heart; Hepatocyte; High Fat Diet; Homeostasis; Hormonal; Hormones; Human; Impairment; Inflammation; Insulin; Insulin Receptor; Insulin Resistance; Intestines; Knockout Mice; Knowledge; Language; Lead; Link; Liver; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Mus; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathway interactions; Peripheral; Physiological; Physiology; Plasma Proteins; Plasmids; Play; Polypeptide Hormones; Protein Family; Proteins; Reagent; Recombinant Proteins; Recombinants; Research Project Grants; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; TNF gene; Testing; Time; Tissues; Transgenic Mice; Weight Gain; Wild Type Mouse; Yang; Yin; Yin-Yang; adipokines; adiponectin; animal data; base; bone; data modeling; diabetic; energy balance; fatty acid oxidation; glucose disposal; glucose metabolism; glucose uptake; human data; improved; in vivo; innovation; insight; insulin sensitivity; insulin sensitizing drugs; lipid metabolism; loss of function; metabolic rate; mouse model; novel; overexpression; paralogous gene; protein function; response; rosiglitazone; tool

Abstract Integrated control of metabolism requires inter-organ communication in the peripheral tissues; this crosstalk is largely orchestrated by secreted hormones. Our long-term goal is to understand hormonal control of energy homeostasis. This proposal is a competitive renewal of a continuing research project focusing on a conserved family of secreted plasma proteins we identified, the C1q/TNF-related proteins (CTRPs). In the last decade, we have provided new and important knowledge on the roles and contributions of various CTRP hormones to whole-body glucose and lipid metabolism. In the next budget cycle, we will focus our studies on CTRP6, a protein with fundamentally different modes of action compared to other CTRPs characterized to date. Our preliminary studies on CTRP6, combined with recent studies of other CTRP family members, has led to the Yin and Yang concept, in which different CTRPs function as positive or negative regulators of substrate metabolism. The central hypothesis, based on gain- and loss-of-function mouse models, is that CTRP6 functions as a negative physiological regulator of glucose metabolism. We propose two specific aims toward understanding the mechanisms by which CTRP6 negatively regulates glucose metabolism at the tissue (Aim 1) and cellular (Aim 2) levels. We expect Aim 1 and Aim 2 to provide critical insights into metabolic gene circuits and signaling networks directly regulated by CTRP6 in adipocytes, skeletal muscle, and liver to control systemic energy metabolism. Since over-activation of the CTRP6-regulated pathways contributes to obesity-linked insulin resistance and diabetes, our studies have the potential to provide insights that lead to innovative strategies to reverse or mitigate metabolic disease outcomes in clinical settings.

摘要 代谢的综合控制需要外周组织中的器官间通讯;这 相声在很大程度上是由分泌的荷尔蒙来协调的。我们的长期目标是了解 能量平衡的荷尔蒙控制。这一提议是一个持续的竞争性更新， 一个研究项目集中在一个保守的家庭分泌的血浆蛋白，我们确定， C1 q/TNF相关蛋白（CTRP）。在过去的十年里，我们提供了新的和重要的 了解各种CTRP激素对全身葡萄糖的作用和贡献， 脂质代谢在下一个预算周期，我们将把研究重点放在CTRP 6上，这是一种蛋白质， 与迄今为止表征的其他CTRP相比，具有根本不同的作用模式。我们 对CTRP 6的初步研究，结合最近对其他CTRP家族成员的研究， 导致了阴和阳的概念，其中不同的CTRP起着积极或消极的作用 底物代谢的调节剂。基于功能获得和丧失的中心假设 在小鼠模型中，CTRP 6作为葡萄糖的负生理调节剂起作用 新陈代谢.我们提出了两个具体的目标，以了解CTRP 6的机制， 在组织（Aim 1）和细胞（Aim 2）水平负调节葡萄糖代谢。我们预计 目标1和目标2提供对代谢基因电路和信号网络的重要见解 在脂肪细胞、骨骼肌和肝脏中由CTRP 6直接调节，以控制全身能量 新陈代谢.由于CTRP 6调节途径的过度激活有助于肥胖相关的 胰岛素抵抗和糖尿病，我们的研究有可能提供见解，从而导致 在临床环境中逆转或减轻代谢疾病结果的创新策略。