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：
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
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/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

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.

项目摘要糖尿病是全球死亡的主要原因，对肌肉骨骼系统。代谢导致进行性骨骼肌损失，功能下降，快速肌纤维萎缩，增加了对伤害和再生的敏感性。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。 NAD+储备会耗尽。基于我们在吡啶核苷酸和代谢调节领域的预临时研究和专业知识，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蛋白酶基转移酶（NAMPT）的功能是主要目标是开发NAMPT NAMPT激活剂以保护骨骼肌免受糖尿病和其他代谢相关为此，我们提出了两个特定目标。糖尿病的骨骼肌肉与P7C3。 NAD/NADH比的强度和相关性，用于改进功能方法将包括功能，生化和分子测量。 NAD/NADH在糖尿病骨骼肌中的基本作用。骨骼肌肉靶向P7C3纳米粒子药物输送系统。体内和体外递送的较高治疗功效。 P7C3的机械基础，涉及骨骼肌肉的糖尿病复杂性。使用肌肉特异性敲除小鼠模型沿沿沿沿沿沿沿沿线的HNF1βFlox的小鼠模型沿沿着沿沿着沿沿着沿沿沿沿沿沿沿线的肌肉敲除小鼠模型阐明的NAMPT-HNF1β-PPARα沿用HSACRE小鼠评估肝细胞核FACLEAR FACLEAR 1-β（HNF1β）作为新功能的主要作用骨骼肌肉中的代谢模块化。 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。 NAMPT在糖尿病骨骼肌肌肉中的作用和具有新目标HNF1β的新机制的作用与Nampt一起编排，以最佳调节骨骼肌的代谢。