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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：
8635126
负责人：
LUBOV T TIMCHENKO
金额：
$ 17.16万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635126
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 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 public health relevance skeletal muscle wasting therapy development wasting

项目摘要

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 3b (GSK3b) improves skeletal muscle pathology in the DM1 mouse model. We found that the mutant CUG repeats increase enzymatic activity and the levels of GSK3b 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 GSK3b, or with the potent inhibitor of GSK3b, 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 GSK3b activity and by correction of expression of one of the GSK3b substrates, cyclin D3. The correction of cyclin D3 by the inhibition of GSK3b leads to the reduction of the suppressive form of CUGBP1, which causes skeletal muscle atrophy and weakness. Since these GSK3 inhibitors reduce both GSK3b and GSK3a, Specific Aim 1 of this proposal will examine if a genetic reduction of GSK3b in HSALR mice will lead to the reduction of DM1 muscle pathology. To achieve the genetic reduction of GSK3b, muscle specific GSK3b knock out (SbKO) mice are crossed with HSALR mice, producing HSALR/SbKO mice. Improvement of muscle pathology in HSALR/SbKO 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 GSK3b are used in the pre-clinical studies for other diseases, the application of these inhibitors might accelerate the development of DM1 therapy using GSK3b inhibitors. The increase of GSK3b in DM1 muscle suggests that other substrates of GSK3b might be also altered in DM1. Patients with DM1 have a predisposition to Type 2 Diabetes (T2D). It is known, that GSK3b is increased in skeletal muscle of patients with T2D. The increase of GSK3b 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 GSK3b 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 GSK3b 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.

1型肌强直性营养不良症（DM1）是一种以骨骼肌为特征的复杂神经肌肉疾病