Pathophysiology and Treatment of Recessive RYR1 Related Myopathy

隐性 RYR1 相关肌病的病理生理学和治疗

基本信息

批准号：
10640863
负责人：
JAMES J DOWLING
金额：
$ 40.35万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-29 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640863
关键词：
Acute Alleles Animal Model Cessation of life Characteristics Chemicals Chronic Clinical Coupling Data Disease Drug Targeting Epigenetic Process Exhibits Exons FDA approved Functional disorder GDF8 gene Genes Goals Growth Heterozygote High Prevalence Histone Deacetylase Histone Deacetylase Inhibitor Human Characteristics Inheritance Patterns Inherited Intervention Messenger RNA Modeling Molecular Chaperones Mus Muscle Muscle Fibers Muscle Weakness Mutate Mutation Myopathy Outcome Outcome Measure Output Pathogenesis Patients Pharmaceutical Preparations Phenocopy Point Mutation Pre-Clinical Model Preclinical Testing Receptor Gene Respiratory Insufficiency Ryanodine Receptor Calcium Release Channel Sampling Sarcoplasmic Reticulum Severities Severity of illness Skeletal Muscle Sodium Testing Therapeutic Therapeutic Intervention Treatment Efficacy disability disease phenotype early onset ebselen effective therapy efficacy evaluation endoplasmic reticulum stress epigenome infancy inhibitor inhibitor therapy insight mortality mouse model mutant novel premature primary outcome protein degradation protein expression protein folding protein function receptor receptor expression receptor function secondary outcome therapeutic evaluation therapy design therapy development

项目摘要

Mutations in the gene that encodes the skeletal muscle type I ryanodine receptor (RYR1) result in a wide range of muscle disorders that collectively comprise the most common cause of non-dystrophic myopathy. The most severe cases of RYR1-related myopathy (RYR1-RM) exhibit a recessive pattern of inheritance and present in infancy with muscle hypotrophy, weakness, respiratory insufficiency, short stature, and a marked reduction in RYR1 protein expression in muscle. Despite their severity, high prevalence and association with significant disability and early mortality, there are no treatments or disease-modifying therapies for RYR1-RM. A major barrier to therapy development has been the lack of an animal model that mirrors the early onset and clinical severity of recessive RYR1-RM. To overcome this barrier, we developed two mouse models of recessive RYR1-RM that pheno-copy key characteristics of the human disorder including myofiber hypotrophy, reduced muscle/body mass, muscle weakness, markedly reduced RYR1 expression, and premature death. The scientific premise of this proposal is that these new mouse models of RYR1-RM provide a unique opportunity to explore the underlying patho-mechanisms of RYR1-RM and test the therapeutic efficacy of mechanism-based interventions. The overall goal of the project is to elucidate the patho-mechanisms responsible for muscle dysfunction in recessive RYR1-RM and to develop and validate effective treatments. We hypothesize that reduced folding/stability of mutated RYR1 homotetramers results in increased RYR1 protein degradation that markedly reduces RYR1 expression, and that even a modest increase in either RYR1 expression or function will ameliorate the myopathy and prolong survival. Furthermore, we also hypothesize that reduced myofiber size in RYR1-RM is a key aspect of disease pathogenesis, that hypotrophy is due to epigenetic abnormalities, and that drugs that target the epigenome or promote muscle growth can ameliorate the disease phenotype. The validity of these hypotheses will rigorously evaluated in three specific aims. Aim 1 will characterize RYR1 expression, function and myopathy in two mouse models of severe, recessive RYR1-RM and assess the therapeutic potential of systemic treatment with ebselen, an FDA-approved drug and known RYR1 activator. Aim 2 will elucidate the mechanism(s) for reduced RYR1 expression in our mouse models of RYR1-RM mice and evaluate the therapeutic efficacy of systemic treatment with a chemical chaperone and ER stress inhibitor (4PBA). Aim 3 will determine the mechanisms leading to muscle hypotrophy in RYR1-RM mice and test the potential of treatment with either HDAC inhibitors or modulators of myofiber size. The results of these studies will provide novel insights into the patho-mechanisms responsible for reduced RYR1 expression and muscle fiber hypotrophy in recessive RYR1-RM and determine the therapeutic potential of several mechanism-based interventions designed to enhance RYR1 function, reduce RYR1 degradation, and limit muscle hypotrophy in pre-clinical models of recessive RYR1-RM.

编码骨骼肌I型ryanodine受体（RYR1）的基因中的突变导致广泛的范围共同构成非疾病肌病的最常见原因的肌肉障碍。最多 RYR1相关肌病（RYR1-RM）的严重病例表现出隐性的遗传模式，并存在于肌肉萎缩，无力，呼吸功能不全，身材矮小的婴儿期和明显的减少 RyR1蛋白在肌肉中的表达。尽管它们的严重程度，高流行和与重大的关联残疾和早期死亡率，没有治疗方法或修改疾病的RYR1-RM疗法。专业治疗发展的障碍是缺乏反映早期和临床的动物模型隐性ryr1-rm的严重程度。为了克服这一障碍，我们开发了两种隐性鼠标模型 RYR1-RM，人类疾病（包括肌生纤维萎缩）的平球副本关键特征减少肌肉/体重，肌肉无力，显着降低了RYR1表达和过早死亡。该提案的科学前提是这些新的RYR1-RM的鼠标模型提供了独特的探索RYR1-RM的潜在病情机制并测试治疗功效的机会基于机制的干预措施。该项目的总体目标是阐明病情机制负责隐性RYR1-RM中的肌肉功能障碍，并开发和验证有效的治疗方法。我们假设突变的RYR1同二探子的折叠/稳定性降低导致RYR1增加蛋白质降解显着降低了RyR1的表达，即使这两种RYR1也适度增加表达或功能将改善肌病和延长生存。此外，我们还假设降低RYR1-RM中的肌纤维大小是疾病发病机理的关键方面，该萎缩是由于表观遗传异常，靶向表观基因组或促进肌肉生长的药物可以改善疾病表型。这些假设的有效性将以三个特定目的进行严格评估。 AIM 1将在两种严重，隐性的小鼠模型中表征RYR1表达，功能和肌病 RYR1-RM并评估用FDA批准的药物Ebselen进行全身治疗的治疗潜力和已知的RYR1激活剂。 AIM 2将阐明小鼠中RYR1表达降低的机制 RYR1-RM小鼠的模型，并评估使用化学物质治疗的治疗功效伴侣和ER应力抑制剂（4PBA）。 AIM 3将确定导致肌肉萎缩的机制在RYR1-RM小鼠中，并测试用HDAC抑制剂或肌纤维调节剂的治疗潜力尺寸。这些研究的结果将提供对负责的病情机制的新见解。 RYR1表达和肌肉纤维降低了隐性RyR1-RM并确定治疗性旨在增强RYR1功能的几种基于机制的干预措施的潜力，降低RYR1 降解，并限制隐性RYR1-RM临床前模型中的肌肉萎缩。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy.

DOI：
10.1242/dmm.049437
发表时间：
2022-05-01
期刊：
DISEASE MODELS & MECHANISMS
影响因子：
4.3
作者：
Espinosa, Karla G.;Geissah, Salma;Groom, Linda;Volpatti, Jonathan;Scott, Ian C.;Dirksen, Robert T.;Zhao, Mo;Dowling, James J.
通讯作者：
Dowling, James J.

Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy.