Protecting the Diabetic Skeletal Muscle by Nampt Activation

项目摘要 糖尿病是美国和世界范围内的主要死因，对人类健康造成有害后果。 肌肉骨骼系统不管血糖控制如何，骨骼肌糖尿病表现为改变了 代谢导致进行性骨骼肌损失、功能下降、快速型肌纤维萎缩， 增加对损伤和受损再生的敏感性。建议我们发展理解， 与代谢改变和骨骼肌风险增加相关的直接因果现象， 糖尿病我们已经确定，糖尿病导致肌肉NADH水平沿着显著升高， 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 假设糖尿病骨骼肌中NAD/NADH比率降低导致肌肉萎缩， 功能，并且烟酰胺磷酸核糖基转移酶（Nampt）的活化是保护性的。主要目的 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疾病的影响。 综合征为此，我们提出两个具体目标。在具体目标1A下，我们将挽救 糖尿病骨骼肌P7 C3。我们将利用糖尿病小鼠模型，以确定减少肌肉活动 Nampt、NAD/NADH比值与功能改善的相关性。实验 方法将包括功能，生物化学和分子测量。这些实验将建立 NAD/NADH在糖尿病骨骼肌中的基本作用。具体目标1B将开发创新的 骨骼肌靶向P7 C3纳米颗粒给药系统。肉毒碱-P7 C3颗粒将允许 用于体内和体外递送的更高的治疗功效。在具体目标2A下，我们将调查 P7 C3在骨骼肌中对抗糖尿病并发症的机制基础。信号通路涉及 将使用HNF 1 βflox沿着的肌肉特异性敲除小鼠模型阐明Nampt-HNF 1 β-PPARα 目的：探讨肝细胞核因子1-β（HNF 1 β）作为一种新的功能性肝细胞因子， 骨骼肌中的代谢调节剂。最后，在子目标2B中，我们将研究 Nampt的药理学及其对SIRT 1、HNF 1 β沿着脂质的靶向和鉴定的特异性 参与肌肉保护的信号介质。总的来说，项目的完成将决定因果关系 Nampt在糖尿病骨骼肌中的作用，并通过新的靶点HNF 1 β阐明新的机制， 与Nampt协调以最佳地调节骨骼肌中的代谢。

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.