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开发依赖于准确反映人类疾病的动物模型。Duchenne肌营养不良症(DMD)是由于非功能性dystrophin蛋白产物的表达引起的，而Becker肌营养不良症(BMD)是由于部分功能蛋白产物的表达或dystrophin含量不足引起的。目前， Dystrophin缺陷小鼠和狗被用来制作营养不良症(BDMD)的模型。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很大贡献，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，以更准确地概括在人类中观察到的BDMD表型。我们已经确定了一系列有高应激诱导死亡率的猪，我们已经将这种缺陷映射到了dystrophin，并显示出受影响动物肌肉中dystrophin积累的急剧减少。我们的长期目标是对BDMD有详细的了解，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实现长期目标。本申请的目的是全面描述猪的骨密度模型，以补充和扩展现有模型的实用价值。根据我们的初步数据，我们的中心假设是，dystrophin表达不足的猪的表型与人类经历的中到重度骨密度相当。我们提出这项研究的理由是，猪在生理和系统发育上与人类比狗或老鼠更相似，因此更准确地反映了在人类身上观察到的疾病进展。在这个项目完成后，我们将有：1)用于翻译研究的猪BMD模型的特征；2)将致病突变传递给NIH小型猪，这将增加其作为翻译模型的相关性。这项研究具有创新性，因为它专注于一种新的动物模型--猪的BMD模型。此外，初步数据显示，疾病表型与最近发现的导致Dstrophin表达受抑的单核苷酸多态密切相关。这项拟议的研究意义重大，因为它将提供一个亟需的大型动物模型的特征，预计该模型将比现有的动物模型更能反映人类疾病。目标1和目标2中提出的工作的预期结果是对肌营养不良蛋白缺乏的骨骼肌疾病进展的全面表征。 此外，还对未来用作BDMD的翻译研究模型进行了初步验证。这种模式将产生重要的积极影响，因为它将为研究人员提供BDMD研究亟需的替代和比较模式，并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.