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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.

项目总结