Inhibition of GSK3 beta as potential therapy for DM1

抑制 GSK3 beta 作为 DM1 的潜在疗法

• 批准号: 8930071
• 负责人: LUBOV T TIMCHENKO
• 金额: $ 19.88万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930071
• 关键词: 19q; 3' Untranslated Regions; Affect; Basic Science; Biopsy; Breeding; Cardiac; Cataract; Cell Nucleus; Cells; Chromosomes; Clinical; Complex; Cytoplasmic Granules; Data; Defect; Development; Diabetes Mellitus; Disease; FDA approved; Fasting; Fatigue; Fiber; Fibrosis; Functional disorder; Genes; Genetic; Genetic Translation; Glucose; Glucose Intolerance; Glycogen; Glycogen (Starch) Synthase; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Health; Histopathology; Homeostasis; Inflammation; Insulin; Insulin Resistance; Knock-in Mouse; Knock-out; Knowledge; Lead; Left; Lithium; Messenger RNA; Modeling; Moods; Mus; Muscle; Muscle Cells; Muscle Proteins; Muscle Weakness; Muscular Atrophy; Myopathy; Myotonia; Myotonic Dystrophy; Neurologic; Neuromuscular Diseases; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Predisposition; Prevalence; Production; Protein Biosynthesis; RNA; RNA Processing; RNA Splicing; RNA-Binding Proteins; Role; Skeletal Muscle; Stress; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transgenic Mice; Translating; aged; base; blood glucose regulation; cyclin D3; feeding; glucose metabolism; glucose tolerance; grasp; high risk; improved; inhibitor/antagonist; insulin sensitivity; insulin tolerance; mouse model; muscle strength; mutant; preclinical study; skeletal muscle wasting; therapy development; wasting

DESCRIPTION (provided by applicant): Myotonic Dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, myotonia and insulin resistance. DM1 is caused by the expanded RNA CUG repeats that misregulate RNA homeostasis through RNA-binding proteins, CUGBP1 and MBNL1. Therapeutic approaches for DM1 reducing toxicity of the mutant CUG repeats are actively developing; however, there is still no cure for DM1. Here we propose to examine the hypothesis that the genetic inhibition of Glycogen Synthase kinase 3? (GSK3?) improves skeletal muscle pathology in the DM1 mouse model. We found that the mutant CUG repeats increase enzymatic activity and the levels of GSK3? in skeletal muscle biopsies from patients with DM1 and in skeletal muscle of the DM1 mouse model, HSALR mice. We showed that the treatments of HSALR mice with lithium (Li), a known inhibitor of GSK3?, or with the potent inhibitor of GSK3?, TDZD-8, reduce the number of fibers with internal nuclei, increase grip strength and reduce myotonia. Such improvement of muscle pathology in the HSALR mice was accompanied by the normalization of GSK3? activity and by correction of expression of one of the GSK3? substrates, cyclin D3. The correction of cyclin D3 by the inhibition of GSK3??leads to the reduction of the suppressive form of CUGBP1, which causes skeletal muscle atrophy and weakness. Since these GSK3 inhibitors reduce both GSK3? and GSK3?, Specific Aim 1 of this proposal will examine if a genetic reduction of GSK3? in HSALR mice will lead to the reduction of DM1 muscle pathology. To achieve the genetic reduction of GSK3??? muscle specific GSK3? knock out (S?KO) mice are crossed with HSALR mice, producing HSALR/S?KO mice. Improvement of muscle pathology in HSALR/S?KO mice will provide a background for the development of therapy for DM1 patients which will be based on the inhibitors of GSK3. Since Li is approved by FDA to treat mood diseases and because potent inhibitors of GSK3? are used in the pre-clinical studies for other diseases, the application of these inhibitors might accelerate the development of DM1 therapy using GSK3??inhibitors. The increase of GSK3? in DM1 muscle suggests that other substrates of GSK3? might be also altered in DM1. Patients with DM1 have a predisposition to Type 2 Diabetes (T2D). It is known, that GSK3? is increased in skeletal muscle of patients with T2D. The increase of GSK3? in T2D causes a reduction of the activity of glycogen synthase that leads to the reduction of the glycogen synthesis and alteration of glucose metabolism. We hypothesize that the increase of GSK3? in skeletal muscle of HSALR mice causes glucose and insulin insensitivity and predisposition to T2D. This hypothesis will be tested in the Aim 2. In summary, our study will show if the genetic inhibition of GSK3? might improve muscle pathology and enhance insulin and glucose sensitivity in the DM1 mouse model. The knowledge, obtained in mouse model of DM1, will be translated to the clinical therapy of DM1.

描述(申请人提供)：强直性肌营养不良1型(DM1)是一种复杂的神经肌肉疾病，以骨骼肌萎缩、虚弱、肌强直和胰岛素抵抗为特征。DM1是由扩展的RNA CUG重复序列引起的，该重复序列通过RNA结合蛋白CUGBP1和MBNL1错误地调节RNA动态平衡。减少突变的CUG重复序列对DM1毒性的治疗方法正在积极发展；然而，DM1仍然没有治愈的方法。在这里，我们建议检验一种假设，即糖原合成酶激酶3？(GSK3？)改善DM1小鼠模型的骨骼肌病理。我们发现，突变的CUG重复序列增加了酶的活性，GSK3？在DM1患者的骨骼肌活检中，以及在DM1小鼠模型HSALR小鼠的骨骼肌中。我们发现，用已知的GSK3？抑制剂锂(Li)或GSK3？的强效抑制剂TDZD-8处理HSALR小鼠，可减少内核纤维的数量，增加握力，减少肌张力。HSALR小鼠肌肉病理的这种改善伴随着GSK3？活性和纠正其中一个GSK3的表达？底物，细胞周期蛋白D3。通过抑制GSK3？来纠正细胞周期蛋白D3，导致CUGBP1抑制形式的减少，从而导致骨骼肌萎缩和虚弱。因为这些GSK3抑制剂降低了两种GSK3？和GSK3？，这项提案的具体目标1将检查GSK3？在HSALR小鼠中会导致DM1肌肉病理减轻。以实现GSK3基因的减少？肌肉特异性GSK3？将基因敲除小鼠(S？KO)与HSALR小鼠杂交，产生HSALR/S？KO小鼠。HSALR/S KO小鼠肌肉病理的改善将为以GSK3抑制剂为基础的DM1患者治疗的发展提供背景。既然LI被FDA批准用于治疗情绪疾病，因为GSK3的有效抑制剂？用于其他疾病的临床前研究，这些抑制剂的应用可能会加速使用GSK3？抑制剂进行DM1治疗的发展。GSK3？在DM1肌肉中提示GSK3？可能也会在DM1中更改。DM1患者易患2型糖尿病(T2D)。众所周知，那就是GSK3？在T2D患者的骨骼肌中是增加的。GSK3？T2D导致糖原合成酶活性降低，导致糖原合成减少，糖代谢改变。我们假设GSK3的增加？在HSALR小鼠的骨骼肌中，可导致葡萄糖和胰岛素不敏感以及对T2D的易感性。这一假说将在目标2中得到验证。综上所述，我们的研究将表明GSK3的遗传抑制是否？可能改善DM1小鼠模型的肌肉病理并增强胰岛素和葡萄糖敏感性。在DM1小鼠模型中获得的知识将转化为DM1的临床治疗。