Characterization of a novel translational model for Becker muscular dystrophy

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发展取决于准确反映人类疾病的动物模型。杜氏肌营养不良症（DMD）是由非功能性肌营养不良蛋白产物的表达引起的，而贝克肌营养不良症（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。目前， 肌营养不良蛋白缺陷的小鼠和狗用于模拟肌营养不良蛋白病（BDMD）。毫无疑问，这些模型对我们目前对BDMD的理解和治疗干预的发展做出了重大贡献，但是，由于每种模型都有局限性，因此都不能代表理想的模型。因此，仍然迫切需要开发和表征更准确地再现在人类中观察到的BDMD表型的动物模型。我们已经确定了一系列具有高应激诱导死亡率的猪，我们已经将缺陷映射到肌营养不良蛋白，并显示受影响动物肌肉中肌营养不良蛋白积累的急剧减少。 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，实现我们的长期目标受到现有动物模型的限制。本申请的目的是充分表征补充和扩展当前可用模型实用性的猪BMD模型。基于我们的初步数据，我们的中心假设是，肌营养不良蛋白表达不足的猪将具有与人类中经历的中度至重度BMD相当的表型。我们提出这项研究的理由是，猪在生理学和遗传学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。在这个项目完成后，我们将：1）表征用于转化研究的BMD猪模型，2）将致病突变传递给NIH小型猪，这将增加其作为转化模型的相关性。 这项研究是创新性的，因为它集中在一个新的动物模型，骨密度的猪模型。此外，初步数据显示，疾病表型与最近发现的导致抗肌萎缩蛋白表达抑制的单核苷酸多态性密切相关。拟议的研究是重要的，因为它将提供一个急需的大型动物模型，预计更密切地反映人类疾病比目前可用的动物模型的表征。在目标1和2中提出的工作的预期成果是从肌营养不良蛋白不足的骨骼肌疾病进展的充分表征 猪以及对未来用作BDMD转化研究模型的初步验证。这种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。

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.