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Micro RNAs as biomarkers and therapeutic targets in myotubular myopathy

Micro RNA 作为肌管性肌病的生物标志物和治疗靶点

基本信息

批准号：
10005607
负责人：
MATTHEW Scott ALEXANDER
金额：
$ 2万
依托单位：
HOSPITAL FOR SICK CHLDRN (TORONTO)
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005607
关键词：
Address Atrophic Biological Markers Biometry Biopsy Cell physiology Centronuclear myopathy Childhood Clinical Clinical Treatment Clinical Trials Complex Coupling Data Defect Dependence Development Disease Disease Progression Down-Regulation Duchenne muscular dystrophy Dynamin 2 Elements Evaluation Fishes Future Gene Expression Generations Genes Goals Histopathology Intervention Knowledge Link Mediating Mediator of activation protein Medical Methodology MicroRNAs Monitor Morbidity - disease rate Mus Muscle Mutation Myopathy Nature Neuromuscular Diseases Outcome Measure Pathogenesis Pathology Patients Pharmacology Phenotype Phosphoric Monoester Hydrolases Population Process Proto-Oncogene Proteins c-akt Reagent Research Personnel Resources Serum Severity of illness Signal Pathway Signal Transduction Small RNA Sorting - Cell Movement Structural defect Structure Symptoms Testing Therapeutic Therapeutic Intervention Time Transgenic Mice Transgenic Organisms Translating Translations Triad Acrylic Resin Untranslated RNA Validation Ventilator Wheelchairs Work base biomarker validation circulating microRNA clinical translation congenital myopathy disability experience improved loss of function mutation mortality mouse model muscular structure myotubularin novel novel therapeutic intervention overexpression potential biomarker pre-clinical response biomarker targeted treatment therapeutic target therapy development translation to humans treatment effect treatment response treatment strategy

项目摘要

PROJECT SUMMARY Myotubular myopathy is a fatal neuromuscular disease associated with severe morbidities (including wheelchair and ventilator dependence) and early mortality. There are critical barriers hindering treatment for this devastating disease. These include the need to uncover new therapeutic strategies, particularly ones with applicability for a broader spectrum of congenital myopathies, and to develop non-invasive biomarkers that correlate with treatment response and are thus suitable for use in clinical trials. Our overarching goal is to translate therapies for MTM. In this proposal, we will address this goal by establishing the first serum biomarker for MTM and identifying a novel therapeutic approach with broad treatment potential. MTM is an X-linked disorder caused by mutations in MTM1, a phosphatase that regulates endosomal sorting. We have shown that MTM1 mutation results in disruption of the triad, a muscle structure responsible for excitation-contraction coupling, and that triad disorganization is a critical driver of MTM pathogenesis. Several groups have demonstrated that myofiber hypotrophy is also an important contributor to MTM pathology. While the precise mechanisms underlying these changes remain to be elucidated, overexpression of DNM2 is a key driver of the triad defects, and unbalanced AKT-TOR pathway signaling is associated with the reduced myofiber size. In this study, we propose a treatment aimed at targeting and correcting these defects. MicroRNAs (miRNAs) are small, non-coding RNAs that modulate gene expression and serve as important regulators of myriad cellular processes. MiRNAs are emerging as both treatment effect biomarkers and potential therapeutics. In several disorders (including other muscle diseases), circulating miRNAs correlate with disease severity and treatment response, and are under consideration as biomarkers in clinical trials. The miRNAs miR-486 and miR-133a have direct relevance to MTM pathogenesis. We have shown that miR- 486 regulates myofiber size by rebalancing AKT signaling, and others have demonstrated that miR-133a directly down-regulates DNM2. These miRNAs are thus attractive as potential therapeutic targets, a concept validated by our demonstration of miR-486 overexpression as a treatment strategy for DMD. In preliminary data, we profiled miRNAs from MTM mouse muscle and found significant changes in 50 miRNAs including downregulation of miR-486 and miR-133a. Based on this, we hypothesize that changes in the levels of miRNAs will correlate with disease status and treatment response, and thus function as an ideal non-invasive biomarker for MTM. Further, we predict that restoring expression of miR-486 and miR-133a will increase myofiber size and reverse triad defects respectively, and thus rescue the MTM phenotype. We will test these hypotheses using rigorous methodology in the murine model of MTM. Successful completion of our study will identify the first biomarker of MTM suitable for clinical translation, and establish a novel treatment with applicability to muscle diseases that feature myofiber hypotrophy and/or triad defects.

项目概要肌管性肌病是一种致命的神经肌肉疾病，伴有严重的发病率（包括轮椅和呼吸机依赖）和早期死亡。存在阻碍治疗的关键障碍这种毁灭性的疾病。其中包括需要发现新的治疗策略，特别是那些具有以下特点的治疗策略：适用于更广泛的先天性肌病，并开发非侵入性生物标志物与治疗反应相关，因此适合用于临床试验。我们的总体目标是翻译 MTM 的疗法。在本提案中，我们将通过建立第一个血清来实现这一目标 MTM 的生物标志物并确定具有广泛治疗潜力的新型治疗方法。 MTM 是一种由 MTM1 突变引起的 X 连锁疾病，MTM1 是一种调节内体分选的磷酸酶。我们已经证明 MTM1 突变会导致三联体的破坏，三联体是一种肌肉结构，负责兴奋-收缩耦合，三联体解体是 MTM 发病机制的关键驱动因素。一些研究小组已经证明，肌纤维萎缩也是 MTM 病理学的一个重要因素。尽管这些变化背后的确切机制仍有待阐明，DNM2 的过度表达是关键三联体缺陷的驱动因素，不平衡的 AKT-TOR 通路信号传导与减少肌纤维大小。在这项研究中，我们提出了一种旨在针对和纠正这些缺陷的治疗方法。 MicroRNA (miRNA) 是小的非编码 RNA，可调节基因表达并发挥重要作用。无数细胞过程的调节者。 miRNA 正在作为治疗效果生物标志物和潜在的治疗方法。在多种疾病（包括其他肌肉疾病）中，循环 miRNA 与与疾病严重程度和治疗反应有关，并且正在考虑作为临床试验中的生物标志物。 miRNA miR-486 和 miR-133a 与 MTM 发病机制直接相关。我们已经证明 miR- 486 通过重新平衡 AKT 信号传导来调节肌纤维大小，其他人已经证明 miR-133a 直接下调 DNM2。因此，这些 miRNA 作为潜在的治疗靶点很有吸引力，这是一个概念我们将 miR-486 过度表达作为 DMD 的治疗策略进行了验证。在初步数据中，我们分析了 MTM 小鼠肌肉中的 miRNA，发现 50 个区域发生了显着变化。 miRNA 包括 miR-486 和 miR-133a 的下调。基于此，我们假设变化 miRNA 的水平将与疾病状态和治疗反应相关，因此可以作为理想的 MTM 的非侵入性生物标志物。此外，我们预测恢复 miR-486 和 miR-133a 的表达将分别增加肌纤维尺寸和逆转三联体缺陷，从而挽救 MTM 表型。我们将在 MTM 小鼠模型中使用严格的方法测试这些假设。顺利完成我们的研究将确定第一个适合临床转化的 MTM 生物标志物，并建立一种新的 MTM 生物标志物。适用于以肌纤维营养不良和/或三联缺陷为特征的肌肉疾病的治疗。