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（由申请人提供）：1型强直性肌营养不良症（DM 1）是一种复杂的神经肌肉疾病，其特征为骨骼肌萎缩、无力、肌强直和胰岛素抵抗。DM 1是由扩增的RNA CUG重复序列引起的，该重复序列通过RNA结合蛋白CUGBP 1和MBNL 1错误调节RNA稳态。DM 1降低突变CUG重复的毒性的治疗方法正在积极开发;然而，仍然没有治愈DM 1。在这里，我们建议检查的假设，遗传抑制糖原合成酶激酶3？(GSK3?)改善DM 1小鼠模型中的骨骼肌病理学。我们发现，突变CUG重复增加酶的活性和水平的GSK 3？在来自DM 1患者的骨骼肌活组织检查和DM 1小鼠模型（HSALR小鼠）的骨骼肌中。我们发现，用锂（Li）（一种已知的GSK 3？抑制剂）治疗HSALR小鼠，或使用强效的GSK 3？抑制剂，TDZD-8，减少具有内部核的纤维的数量，增加握力并减轻肌强直。HSALR小鼠肌肉病理学的这种改善伴随着GSK 3？活性，并通过纠正表达的一个GSK 3？底物，细胞周期蛋白D3。通过抑制GSK 3？导致CUGBP 1的抑制形式减少，这导致骨骼肌萎缩和虚弱。由于这些GSK 3抑制剂减少两个GSK 3？GSK3？本提案的具体目标1将检查是否GSK 3的遗传减少？在HSALR小鼠中的作用将导致DM 1肌肉病理学的减少。为了实现GSK 3基因的减少？肌肉特异性GSK 3？击倒（S？KO）小鼠与HSALR小鼠杂交，产生HSALR/S？KO小鼠。改善HSALR/S的肌肉病理学？KO小鼠将为基于GSK 3抑制剂的DM 1患者治疗的开发提供背景。由于李是由FDA批准治疗情绪疾病，因为有效的抑制剂GSK 3？在其他疾病的临床前研究中使用，这些抑制剂的应用可能会加速使用GSK 3？抑制剂的增加GSK 3？在DM 1肌肉表明，其他底物的GSK 3？也可能在DM 1中发生变化。DM 1患者有2型糖尿病（T2 D）的易感性。据了解，GSK 3？在T2 D患者的骨骼肌中增加。增加GSK 3？在T2 D中的糖皮质激素缺乏引起糖原合酶活性的降低，这导致糖原合成的减少和葡萄糖代谢的改变。我们推测，增加GSK 3？在HSALR小鼠的骨骼肌中，引起葡萄糖和胰岛素不敏感性和T2 D的易感性。这一假设将在目标2中得到检验。总之，我们的研究将表明，如果GSK 3的遗传抑制？可能改善肌肉病理学，并增强DM 1小鼠模型的胰岛素和葡萄糖敏感性。在DM 1小鼠模型中获得的知识将转化为DM 1的临床治疗。