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

金毛寻回犬肌肉萎缩症的关节挛缩：Duchenne M 模型

• 批准号: 8106194
• 负责人: Peter Phuong Nghiem
• 金额: $ 5.75万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8106194
• 关键词: 12 year old; Acute; Age; Age-Months; Atrophic; B-Lymphocytes; Biochemistry; Biological Assay; Biological Markers; Biopsy; Birth; Canis familiaris; Cephalic; Child; Code; Contracture; DNA; Data; Databases; Development; Disease; Duchenne muscular dystrophy; Dystrophin; Enzyme-Linked Immunosorbent Assay; Fellowship; Flexor; Functional disorder; Gastrocnemius Muscle; Genes; Genetic; Genetic Medicine; Genetic Polymorphism; Genomics; Glycoproteins; Goals; Grant; Hereditary Disease; Hip region structure; Histologic; Histology; Histopathology; Human; Hypertrophy; Immunoblotting; In Vitro; Joints; Lesion; Life; Light; Link; Longitudinal Studies; M-cadherin; Measurement; Medical center; Membrane; Messenger RNA; Mitotic Activity; Modeling; Molecular; Molecular Profiling; Molecular Target; Muscle; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Dystrophies; Mutation; Myoblasts; Outcome; Pathogenesis; Patients; Phenotype; Physicians; Play; Postdoctoral Fellow; Process; Protein Isoforms; Proteins; Relative (related person); Research; Research Training; Role; Sartorius Muscle; Serum; Serum Proteins; Severity of illness; Skeletal Muscle; Splint Device; Staining method; Stains; Surface; Surrogate Markers; Symptoms; T-Lymphocyte; Testing; Training Programs; Walking; ankle joint; base; boys; cytokine; digital; disability; indexing; macrophage; male; molecular phenotype; muscle strength; neutrophil; osteopontin; prevent; promoter; protein expression; quadriceps muscle; vastus lateralis; wasting

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.

描述（由申请人提供）：本F32博士后奖学金申请的目标是为儿童国家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培训计划。Nghiem博士将利用杜氏肌营养不良症（DMD）犬模型的纵向研究，研究与关节致残性挛缩发展相关的功能和分子结果。基于本申请中提供的大量初步数据，骨桥蛋白成为分子/功能模型的主要靶标。 DMD是一种X连锁隐性疾病，由肌营养不良蛋白基因突变引起，每3,500名活产男婴中就有1名发生。DMD男孩开始表现出骨骼肌无力的迹象，作为一个年轻的孩子，大多数男孩失去了12岁的步行能力。肌无力和关节挛缩被认为是导致DMD患者姿势不稳定和最终丧失Ambrosion的原因。无力、关节挛缩和身体残疾之间的确切因果关系尚未明确;挛缩可能相当严重，有些感觉是导致截肢的主要原因。 我们提出的研究的目标是更好地定义肌肉无力，关节挛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，在关节角周围的多个肌肉中建立包括肌肉力量、肥大/萎缩和组织病理学的机制模型，并在功能（力量、活动性）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症（GRMD），我们有精确的测量萎缩/肥大，肌肉力量，组织学，关节挛缩，和分子指纹作为年龄和残疾的函数。我们要检验的中心假设是，骨桥蛋白（OPN）对萎缩性骨骼肌与肥大性营养不良性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挛缩进展中发挥核心作用。值得注意的是，OPN多态性已被确定为DMD的主要遗传修饰因子，我们提出的研究将阐明OPN在疾病分子病理生理学中的作用。