Protecting the Diabetic Skeletal Muscle by Nampt Activation

通过 Nampt 激活保护糖尿病骨骼肌

• 批准号: 10368097
• 负责人: Marco Brotto
• 金额: $ 40.79万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368097
• 关键词: Antidiabetic Drugs; Area; Atrophic; Automobile Driving; Biochemical; Carbazoles; Carnitine; Cause of Death; Cell Survival; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Diabetic mouse; Diagnosis; Disease; Drug Delivery Systems; Economic Burden; Encapsulated; Energy Metabolism; Enzymes; Equilibrium; Ethanol; Genes; Glycolates; Goals; Growth; Homeostasis; Impairment; In Vitro; Incidence; Injury; Insulin; Insulin Resistance; Knockout Mice; Link; Lipids; Measurement; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Muscle; Muscle function; Musculoskeletal; Musculoskeletal System; Natural regeneration; New Agents; Niacinamide; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidation-Reduction; PPAR alpha; Pathway interactions; Pharmacology; Play; Predisposition; Regulation; Risk; Role; SIRT1 gene; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal muscle injury; Specificity; Syndrome; Testing; Transferase; Treatment Efficacy; base; biodegradable polymer; blood glucose regulation; diabetic; diet-induced obesity; experimental study; fatty acid oxidation; functional decline; functional improvement; glucose metabolism; glucose tolerance; glycemic control; heart disease risk; hepatic nuclear factor 1; improved; in vivo; innovation; insight; lipid metabolism; mouse model; nanoparticle drug; novel; oxidation; particle; prevent; pyridine nucleotide; reduced muscle strength; skeletal muscle metabolism; skeletal muscle wasting

Project Summary Diabetes is a leading cause of death in the US and worldwide with deleterious consequences to the musculoskeletal system. Regardless of glycemic control, diabetes in skeletal muscle manifests with altered metabolism leading to progressive skeletal muscle loss, functional decline, fast-type myofiber atrophy, increased susceptibility to injury and impaired regeneration. The proposal we develop understanding for the direct causal phenomenon associated with altered metabolism and increased risk to skeletal muscle in diabetes. We have identified that diabetes causes significant elevation in muscle NADH levels along with depleted NAD+ reserves. This phenomenon directly associates with decreased muscle function and damage. Based on our preliminary studies and expertise in the area of pyridine nucleotides and metabolic regulation, we hypothesize that decreased NAD/NADH ratio in the diabetic skeletal muscle leads to decline in muscle function, and activation of nicotinamide phosphoribosyl transferase (Nampt) is protective. The major objective is to develop Nampt activators to protect skeletal muscles from diabetes and other metabolic-related syndromes. For this, we propose two specific aims. Under Specific Aim 1A, we will rescue insulin resistance in diabetic skeletal muscle with P7C3. We will utilize diabetic mouse model to identify decreased muscle activity and strength and the relevance of Nampt, NAD/NADH ratio for improvement of function. The experimental approach will include functional, biochemical and molecular measurements. These experiments will establish the fundamental role of NAD/NADH in diabetic skeletal muscle. Specific Aim 1B will develop the innovative skeletal muscle targeting P7C3 nano particle drug delivery system. The Carnitine-P7C3 particle will allow higher therapeutic efficacy for in vivo and in vitro delivery. Under Specific Aim 2A we will investigate the mechanistic basis of P7C3 against diabetic complications in skeletal muscle. The signaling pathway involving Nampt-HNF1β-PPARα will be elucidated using muscle specific knock out mouse models for HNF1βflox along with HSAcre mice to evaluate the chief role of hepatocyte nuclear factor 1-β (HNF1β) as a new functional metabolic modulator in skeletal muscles. Finally, in Sub aim 2B we will investigate the molecular pharmacology of Nampt and its specificity for targeting and identification of SIRT1, HNF1β along with lipid signaling mediators involved in muscle protection. Overall, completion of the project will determine the causal role of Nampt in diabetic skeletal muscle and unravel novel mechanisms with new targets HNF1β that co- orchestrate with Nampt to optimally regulate metabolism in skeletal muscle.

项目摘要 糖尿病是美国的主要死亡原因，在全球范围内，对 肌肉骨骼系统。不管血糖控制如何，骨骼肌中的糖尿病都会随着改变 代谢导致进行性骨骼肌损失，功能下降，快速肌纤维萎缩， 增加了受伤和再生损害的敏感性。我们对 直接因果现象与改变新陈代谢和骨骼肌风险增加有关 糖尿病。我们已经确定糖尿病在肌肉NADH水平以及 耗尽的NAD+储量。这种现象直接与肌肉功能和损害降低相关。 基于我们在吡啶核苷酸和代谢调节领域的初步研究和专业知识，我们 假设糖尿病骨骼肌肉中NAD/NADH的比例降低会导致肌肉下降 烟酰胺磷酸糖基转移酶（NAMPT）的功能和激活受到保护。主要目标 是开发NAMPT激活剂以保护骨骼肌免受糖尿病和其他代谢相关 综合征。为此，我们提出了两个具体目标。在特定的目标1a下，我们将在 糖尿病骨骼肌肉，带有P7C3。我们将利用糖尿病小鼠模型来识别改善的肌肉活动 和强度以及NAMPT的相关性，NAD/NADH比率改善功能。实验 方法将包括功能，生化和分子测量。这些实验将建立 NAD/NADH在糖尿病骨骼肌中的基本作用。特定目标1B将发展创新 骨骼肌靶向P7C3纳米颗粒药物输送系统。肉碱-P7C3粒子将允许 体内和体外递送的较高治疗效率。在特定目标2a下，我们将调查 P7C3对骨骼肌中糖尿病并发症的机械基础。涉及的信号通路 使用肌肉特异性敲除小鼠模型HNF1βFlox沿着Nampt-HNF1β-PPARα沿 用HSACRE小鼠评估肝细胞核因子1-β（HNF1β）的主要作用 骨骼肌中的代谢调节剂。最后，在子目标2B中，我们将研究分子 NAMPT的药理学及其针对SIRT1，HNF1β的靶向和鉴定的特异性以及脂质 涉及肌肉保护的信号介质。总体而言，项目的完成将确定因果关系 NAMPT在糖尿病骨骼肌和具有新靶标HNF1β的新机制中的作用 与Nampt一起编排，以最佳调节骨骼肌的代谢。