Characterization of a novel translational model for Becker muscular dystrophy

贝克型肌营养不良症新型转化模型的表征

• 批准号: 8583896
• 负责人: JOSHUA T SELSBY
• 金额: $ 22.03万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583896
• 关键词: Address; Affect; Animal Disease Models; Animal Model; Animals; Anus; Becker Muscular Dystrophy; Birth; Body Weight; Breeding; Canis familiaris; Cessation of life; Complement; Data; Death Rate; Defect; Development; Disease; Disease Progression; Disease model; Duchenne muscular dystrophy; Dystrophin; Exons; Family suidae; Fibrosis; Frameshift Mutation; Functional disorder; Future; Genes; Genetic; Goals; Health; Human; Injury; Intervention; Iowa; Knowledge; Longevity; Maps; Mission; Modeling; Molecular; Molecular Biology; Mus; Muscle; Mutation; Nonsense Mutation; Obesity; Outcome; Partner in relationship; Patients; Performance; Phenotype; Physiological; Population; Positioning Attribute; Production; Proteins; Proxy; RNA Splicing; Research; Research Personnel; Resources; Severity of illness; Single Nucleotide Polymorphism; Skeletal Muscle; Skeletal muscle injury; Steroid therapy; Stress; Therapeutic; Therapeutic Intervention; Tissue Sample; Translational Research; Translations; United States National Institutes of Health; Utrophin; Validation; Wheelchairs; Work; base; comparative; disability; disease phenotype; effective intervention; exon skipping; experience; human disease; improved; innovation; male; mdx mouse; mouse model; novel; preclinical study; public health relevance; scale up; therapy development; translational medicine; transmission process; wasting

DESCRIPTION (provided by applicant): The translation of basic biomedical knowledge to the development of effective therapeutic approaches depends on animal models that accurately reflect human diseases. Duchenne muscular dystrophy (DMD) is caused by expression of a nonfunctional dystrophin protein product while Becker muscular dystrophy (BMD) results from expression of a partially functional protein product or insufficient dystrophin content. Currently, dystrophin-deficient mice and dogs are used to model dystrophinopathies (BDMD). Undoubtedly, these models have contributed substantially to our current understanding of BDMD and development of therapeutic interventions, however, neither represents an ideal model as there are limitations to each. Consequently, there remains a critical need to develop and characterize animal models that more accurately recapitulate the BDMD phenotype observed in humans. We have identified a line of pigs that have a high stress-induced death rate and we have mapped the defect to dystrophin and shown a drastic reduction of dystrophin accumulation in muscles from affected animals. Our long-term goal is to achieve a detailed understanding of BDMD to enable development of effective intervention strategies. Unfortunately, achieving our long-term goal is hindered by limitations in currently available animal models. The objective of this application is to fully characterize a porcine model of BMD that complements and extends the utility of currently available models. Based on our preliminary data, our central hypothesis is that pigs with insufficient dystrophin expression will have a phenotype comparable to moderate to severe BMD as experienced in humans. Our rationale for the proposed research is that the pig is physiologically and phylogenetically more similar to humans than is either the dog or mouse and therefore more accurately reflects disease progression as observed in humans. At the completion of this project we will have: 1) characterized a porcine model of BMD for use in translational research and 2) transmitted the causative mutation to an NIH miniature pig, which will increase its relevance as a translational model. This research is innovative because it focuses on a new animal model, a porcine model of BMD. Further, preliminary data shows the disease phenotype is strongly correlated to a recently discovered single nucleotide polymorphism that results in suppressed dystrophin expression. The proposed research is significant because it will provide characterization of a much needed large animal model that is expected to more closely reflect the human disease than currently available animal models. The expected outcomes of work proposed in aims 1 and 2 is a full characterization of disease progression in skeletal muscle from dystrophin-insufficient pigs as well as an initial validation toward future use as a translational research model for BDMD. Such a model will have an important positive impact in that it will provide researchers with a much needed alternative and comparative model for BDMD research and it may prove to be an invaluable resource for pre-clinical studies.

描述（由申请人提供）：将基本生物医学知识转化为有效治疗方法的开发取决于准确反映人类疾病的动物模型。杜氏肌营养不良 (DMD) 是由非功能性肌营养不良蛋白产物的表达引起的，而贝克尔肌营养不良 (BMD) 是由部分功能性蛋白产物的表达或肌营养不良蛋白含量不足引起的。现在， 肌营养不良蛋白缺陷小鼠和狗用于模拟肌营养不良病 (BDMD)。毫无疑问，这些模型对我们目前对 BDMD 的理解和治疗干预措施的发展做出了重大贡献，然而，这两种模型都不是理想的模型，因为每种模型都有局限性。因此，仍然迫切需要开发和表征动物模型，以更准确地重现在人类中观察到的 BDMD 表型。我们已经确定了一系列因应激而导致死亡率较高的猪，并将缺陷与肌营养不良蛋白联系起来，并显示受影响动物肌肉中肌营养不良蛋白的积累急剧减少。 我们的长期目标是详细了解 BDMD，以便制定有效的干预策略。不幸的是，目前可用的动物模型的局限性阻碍了我们长期目标的实现。本应用的目的是全面表征猪的 BMD 模型，以补充和扩展当前可用模型的实用性。根据我们的初步数据，我们的中心假设是，抗肌萎缩蛋白表达不足的猪将具有与人类中度至重度 BMD 相当的表型。我们进行这项研究的理由是，猪在生理学和系统发育上比狗或小鼠更类似于人类，因此更准确地反映了在人类中观察到的疾病进展。该项目完成后，我们将：1）表征用于转化研究的猪 BMD 模型，2）将致病突变传递给 NIH 小型猪，这将提高其作为转化模型的相关性。 这项研究具有创新性，因为它关注的是一种新的动物模型，即猪的 BMD 模型。此外，初步数据显示，该疾病表型与最近发现的单核苷酸多态性密切相关，该多态性导致肌营养不良蛋白表达受到抑制。拟议的研究意义重大，因为它将提供急需的大型动物模型的特征，预计该模型比现有的动物模型更能反映人类疾病。目标 1 和 2 中提出的工作的预期成果是抗肌萎缩蛋白不足引起的骨骼肌疾病进展的完整表征 猪以及对未来用作 BDMD 转化研究模型的初步验证。这样的模型将产生重要的积极影响，因为它将为研究人员提供 BDMD 研究急需的替代和比较模型，并且可能被证明是临床前研究的宝贵资源。