Joint Contractures in Golden Retriever Muscular Dystrophy: A Model for Duchenne M

描述(由申请人提供)：该F32博士后奖学金申请的目标是为国家儿童医学中心遗传医学中心的Peter P.Nghiem博士提供为期三年的遗传学、基因组学和生物化学方面的培训计划。Nghiem博士将利用Duchenne肌营养不良症(DMD)犬模型的纵向研究，研究与关节致残性痉挛发展相关的功能和分子结果。根据应用中提供的大量初步数据，骨桥蛋白成为分子/功能模型的主要靶点。DMD是一种X连锁的隐性遗传性疾病，由dystrophin基因突变引起，每3,500名活男婴中就有1人发生DMD。DMD男孩从小就开始表现出骨骼肌无力的迹象，大多数男孩在12岁时就失去了走路的能力。肌肉无力和关节痉挛被认为是导致DMD姿势不稳定和最终失去行走能力的原因。虚弱、关节痉挛和身体残疾之间的确切因果关系还没有很好的定义；痉挛可以是相当猛烈的，有些人觉得是导致行动不便的主要原因。我们建议的研究的目标是更好地定义肌肉无力、关节收缩和残疾之间的关系作为年龄的函数，并了解真正的肥大、消瘦和肌肉分子特征之间的关系。在DMD中，建立包括肌肉力量、肥大/萎缩和关节周围多个肌肉的组织病理学在内的力学模型，并在功能(力量、运动能力)和分子水平上进行研究是具有挑战性的。在犬DMD模型-金毛猎犬肌营养不良(GRMD)模型中，我们精确测量了萎缩/肥大、肌肉力量、组织学、关节痉挛和分子指纹随年龄和残疾的变化。我们的中心假设是，骨桥蛋白(OPN)对萎缩和肥大的营养不良骨骼肌具有不同的分子后果，并可能在肌力失衡和随后的关节痉挛进展中发挥核心作用。值得注意的是，到目前为止，OPN基因多态性已被确定为DMD的主要遗传修饰因子，我们的研究将有助于阐明OPN在疾病分子病理生理学中的作用。 公共卫生相关性：通过对与进行性关节痉挛相关的功能和分子相关性的研究，我们将更好地了解这种致残症状的发病机制。

DESCRIPTION (provided by applicant): The goal of this F32 post-doctoral fellowship application is to provide a three-year training program in genetics, genomics, and biochemistry for Dr. Peter P. Nghiem, at the Center for Genetic Medicine at Children's National Medical Center. Dr. Nghiem will study the functional and molecular outcomes associated with the development of disabling contractures at a joint, utilizing longitudinal studies of the dog model of Duchenne muscular dystrophy (DMD). Based upon extensive preliminary data presented in the application, the osteopontin protein becomes a major target for the molecular/functional models. DMD is an X-linked recessive disorder caused by mutations in the dystrophin gene and occurs in 1 of 3,500 live male births. DMD boys begin to show signs of skeletal muscle weakness as a young child, with most boys losing the ability to walk by the age of 12 years. Muscle weakness and joint contractures are thought to contribute to postural instability and the ultimate loss of ambulation in DMD. The precise cause/effect relationship between weakness, joint contractures, and physical disability is not well defined; contractures can be quite aggressive, and some feel are a major contribution to loss of ambulation. The goals of our proposed study are to better define the relationship among muscle weakness, joint contractures, and disability as a function of age, and understand the relationships among true hypertrophy, wasting, and muscle molecular signatures. In DMD, it is challenging to build mechanistic models including muscle strength, hypertrophy/atrophy, and histopathology in multiple muscles around a joint angle, and study both at the functional (strength, mobility) and molecular levels. In the canine DMD model, Golden retriever muscular dystrophy (GRMD), we have precise measurements of atrophy/hypertrophy, muscle strength, histology, joint contracture, and molecular fingerprints as a function of age and disability. Our central hypothesis to be tested is that osteopontin (OPN) has differential molecular consequences on wasting vs. hypertrophied dystrophic skeletal muscles and may play a central role in muscle force imbalance and subsequent progression of joint contractures. It is important to note that OPN polymorphisms have been identified as the major genetic modifier of DMD to date, and our proposed research will shed light on the role of OPN in disease molecular pathophysiology. PUBLIC HEALTH RELEVANCE: Through the study of functional and molecular correlates associated with progressive joint contractures, we will provide better understanding of the pathogenesis of this disabling symptom.