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.
|Kornegay, Joe N; Spurney, Christopher F; Nghiem, Peter P et al. (2014) Pharmacologic management of Duchenne muscular dystrophy: target identification and preclinical trials. ILAR J 55:119-49|
|Nghiem, Peter P; Hoffman, Eric P; Mittal, Priya et al. (2013) Sparing of the dystrophin-deficient cranial sartorius muscle is associated with classical and novel hypertrophy pathways in GRMD dogs. Am J Pathol 183:1411-24|
|Kornegay, Joe N; Bogan, Janet R; Bogan, Daniel J et al. (2012) Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies. Mamm Genome 23:85-108|