Regulation of gastrointestinal hormone signaling and metabolism by Neuromedin U

Neuromedin U 对胃肠激素信号传导和代谢的调节

• 批准号: 9889949
• 负责人: Seung K Kim
• 金额: $ 40.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889949
• 关键词: Acute; Address; Alleles; Beta Cell; Biology; Body mass index; Cells; Colon; Coupled; Diabetes Mellitus; Diagnosis; Disease; Drosophila genus; Drosophila melanogaster; Duodenum; Electrophysiology (science); Elements; Endocrine; Enteral; Enterobacteria phage P1 Cre recombinase; Enteroendocrine Cell; Enzyme-Linked Immunosorbent Assay; Equilibrium; Foundations; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Galanin; Gap Junctions; Gastric Bypass; Gastrointestinal Hormones; Gastrointestinal tract structure; Genes; Genetic; Glucagon; Glucose; Health; Homeostasis; Hormones; Human; Hyperglycemia; Hyperinsulinism; In Vitro; Insulin; Intestinal Hormones; Intestines; Investigation; Islet Cell; Islets of Langerhans; Ligands; Link; Lipids; Mammals; Metabolic; Metabolic Control; Metabolism; Methods; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Neuromedin U; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Organ; Organ Culture Techniques; Output; Pancreas; Pathway interactions; Peripheral; Pertussis Toxin; Physiological; Prediabetes syndrome; Production; Regulation; Response Elements; Risk; Role; Signal Pathway; Signal Transduction; Somatostatin; Source; Stomach; Testing; Tissues; Work; bariatric surgery; base; blood glucose regulation; comorbidity; effective therapy; gastrointestinal; hormonal signals; hormone metabolism; ileum; impaired glucose tolerance; in vivo; innovation; insight; insulin secretion; islet; neuromedin U receptor; novel; novel strategies; pancreatic juice; peptide hormone; receptor; response; restoration; type I and type II diabetes

ABSTRACT In obesity and type 2 diabetes mellitus (T2D), polyhormonal dysregulation can culminate in a relative insulin-deficient state. Indirect evidence has recently accumulated for an enteric hormone (called a decretin) that suppresses insulin and enhances glucagon output to promote T2D. A fundamental advance for the field would be the identification of native hormones that normally regulate insulin and glucagon production and secretion by pancreatic islet cells. We recently identified an enteroendocrine decretin signaling pathway in the fruit fly Drosophila melanogaster regulated by nutrient availability, and essential for lipid, glucose and insulin balance. We demonstrated from in vitro studies that the mammalian peptide hormone Neuromedin U (Nmu) and its cognate G protein-coupled receptor, Nmu Receptor 1 (NmuR1) have similar functions. Nmu is produced in enteroendocrine cells concentrated in the stomach, duodenum and ileum. In this proposal we outline several original and novel approaches to investigate how the ligand-receptor pair Nmu/NmuR1 regulate gastrointestinal hormone output. To address these fundamental questions in both in mice and humans, we propose Specific Aims to: 1. Assess the requirement for enteric Nmu in mouse metabolic homeostasis. 2. Decode Nmu signal transduction mechanisms by G proteins and NmuR1 in pancreatic islets. 3. Identify mechanisms regulating NMU signaling in human islets This proposal is also notable for technical innovations in each Aim, including construction of multiple novel mouse strains, and use of new ELISAs to investigate Nmu regulation in mice and humans. Collectively, these state-of-the-art approaches will generate major new insights into the cellular and molecular mechanisms controlling enteroendocrine regulation of metabolism in physiological settings. At a fundamental level, our work should establish regulatory paradigms that interconnect metabolic signaling and regulation of crucial gastrointestinal hormones. Thus, our work should have broad impact by suggesting strategies to diagnose, stratify risk, and treat subsets of humans with diabetes mellitus or important pre-diabetic conditions like obesity and impaired glucose tolerance.

摘要 在肥胖和2型糖尿病(T2D)中，多激素失调可导致亲属 胰岛素缺乏状态。最近有间接证据表明存在一种肠道荷尔蒙(称为衰老激素)。 这抑制了胰岛素，增加了胰高血糖素的产量，从而促进了T2D。该领域的根本性进步 将是确定正常调节胰岛素和胰升糖素产生的本地激素，以及 胰岛细胞分泌。我们最近发现了一条肠内分泌递减素信号通路。 果蝇黑腹果蝇受营养可获得性调节，对脂肪、血糖和胰岛素是必需的 平衡。我们从体外研究中证实，哺乳动物多肽激素Neuromedin U(NMU) 与其同源的G蛋白偶联受体NMU受体1(NmuR1)具有相似的功能。NMU是 产生于集中在胃、十二指肠和回肠的肠内分泌细胞。在这份提案中，我们 概述几种研究配体-受体对NMU/NmuR1如何调节的原创性和创新性方法 胃肠激素输出。 为了解决小鼠和人类的这些基本问题，我们提出了具体的目标：1. 评估肠道NMU对小鼠代谢动态平衡的需求。2.解码NMU信号转导 G蛋白和NmuR1在胰岛中的作用机制。3.确定NMU信令的调控机制 在人类的胰岛中 这一提议在每个目标上的技术创新也是值得注意的，包括构建多部小说 小鼠品系，并使用新的ELISA来研究NMU在小鼠和人类中的调节。总而言之，这些 最先进的方法将对细胞和分子机制产生重大的新见解 在生理环境中控制新陈代谢的肠道内分泌调节。从根本上说，我们的工作 应该建立将代谢信号和关键蛋白的调节联系起来的调节范例 胃肠激素。因此，我们的工作应该产生广泛的影响，通过提出诊断策略， 对风险进行分层，并治疗患有糖尿病或重要的糖尿病前期疾病(如肥胖)的人群 和糖耐量受损。