Protecting the Diabetic Skeletal Muscle by Nampt Activation

通过 Nampt 激活保护糖尿病骨骼肌

基本信息

批准号：
9903303
负责人：
Marco Brotto
金额：
$ 40.91万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
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/9903303
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 Diet 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 Obesity 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 Structure Syndrome Testing Transferase Treatment Efficacy base biodegradable polymer blood glucose regulation diabetic 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

项目摘要

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.

项目概要糖尿病是美国和全世界的主要死亡原因，对人类造成有害后果无论血糖控制如何，骨骼肌糖尿病都会表现为：新陈代谢导致进行性骨骼肌损失、功能下降、快速型肌纤维萎缩，增加对损伤的易感性和受损的再生能力。与代谢改变和骨骼肌风险增加相关的直接因果现象我们已经发现，糖尿病会导致肌肉 NADH 水平显着升高。 NAD+储备耗尽这种现象与肌肉功能下降和损伤直接相关。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，我们糖尿病骨骼肌中 NAD/NADH 比率降低导致肌肉衰退烟酰胺磷酸核糖基转移酶 (Nampt) 的激活具有保护作用。是开发 Nampt 激活剂来保护骨骼肌免受糖尿病和其他代谢相关疾病的影响为此，我们在具体目标 1A 中提出了两个具体目标，即拯救胰岛素抵抗。糖尿病骨骼肌与 P7C3 我们将利用糖尿病小鼠模型来识别肌肉活动减少。 Nampt、NAD/NADH 比率的强度和与功能改善的相关性。这些实验将包括功能、生化和分子测量。 NAD/NADH 在糖尿病骨骼肌中的基本作用特定目标 1B 将开发创新产品。骨骼肌靶向 P7C3 纳米颗粒药物输送系统将允许肉碱-P7C3 颗粒。在特定目标 2A 下，我们将研究体内和体外递送的更高治疗效果。 P7C3 对抗骨骼肌糖尿病并发症的机制基础涉及的信号通路。将使用 HNF1βflox 的肌肉特异性敲除小鼠模型来阐明 Nampt-HNF1β-PPARα 与 HSAcrea 小鼠一起评估肝细胞核因子 1-β (HNF1β) 作为一种新功能的主要作用最后，在子目标 2B 中，我们将研究分子。 Nampt 的药理学及其靶向和识别 SIRT1、HNF1β 以及脂质的特异性总体而言，该项目的完成将确定因果关系。 Nampt 在糖尿病骨骼肌中的作用，并通过新靶点 HNF1β 揭示新机制与 Nampt 协调以最佳地调节骨骼肌的新陈代谢。