Inhibition of GSK3 beta as potential therapy for DM1

抑制 GSK3 beta 作为 DM1 的潜在疗法

基本信息

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
项目类别：
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&apos 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

项目摘要

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（DM1）是一种复杂的神经肌肉疾病，其特征为骨骼肌萎缩、虚弱、肌强直和胰岛素抵抗。 DM1 是由扩展的 RNA CUG 重复序列引起的，这些重复序列通过 RNA 结合蛋白 CUGBP1 和 MBNL1 错误调节 RNA 稳态。减少突变 CUG 重复序列毒性的 DM1 治疗方法正在积极开发中；然而，DM1 仍无法治愈。在这里，我们建议检验糖原合成酶激酶 3 的遗传抑制？（GSK3？）改善 DM1 小鼠模型中的骨骼肌病理学。我们发现突变的 CUG 重复序列增加了酶活性和 GSK3？ DM1 患者的骨骼肌活检和 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 对 HSALR 小鼠进行治疗，可以减少具有内部细胞核的纤维数量，增加握力并减少肌强直。 HSALR 小鼠肌肉病理学的这种改善伴随着 GSK3？活性并通过校正 GSK3 之一的表达？底物，细胞周期蛋白D3。通过抑制GSK3来校正细胞周期蛋白D3会导致CUGBP1的抑制形式减少，从而导致骨骼肌萎缩和无力。既然这些 GSK3 抑制剂同时降低了 GSK3？和 GSK3？，该提案的具体目标 1 将检查 GSK3？的基因减少是否？ HSALR 小鼠中的 DM1 肌肉病理学减少。实现GSK3的基因还原？？？肌肉特异性 GSK3？基因敲除 (S?KO) 小鼠与 HSALR 小鼠杂交，产生 HSALR/S?KO 小鼠。 HSALR/S?KO 小鼠肌肉病理学的改善将为开发基于 GSK3 抑制剂的 DM1 患者治疗提供背景。既然 Li 被 FDA 批准用于治疗情绪疾病并且是 GSK3 的强效抑制剂？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的增加？ DM1 肌肉中是否存在 GSK3 的其他底物？ DM1 中也可能会发生变化。 DM1 患者有 2 型糖尿病 (T2D) 的倾向。据了解，GSK3？ T2D 患者的骨骼肌有所增加。 GSK3的增加？ T2D 会导致糖原合酶活性降低，从而导致糖原合成减少和葡萄糖代谢改变。我们假设GSK3的增加？ HSALR 小鼠骨骼肌中的 HSALR 会导致葡萄糖和胰岛素不敏感以及 T2D 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 GSK3 的基因抑制是否有效？可能会改善 DM1 小鼠模型的肌肉病理学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。