The long term objective of this research is to understand the structure and function of dystrophin, the protein product of the Duchenne muscular dystrophy gene. The strategy proposed to attain this goal is to identify the cytoskeletal proteins which interact with dystrophin as well as with the dystrophin-glycoprotein complex in rabbit skeletal muscle.
Five specific aims are proposed: First, the F-actin binding properties of purified dystrophin-glycoprotein complex will be studied. A cosedimentation assay will be used to quantitatively define the binding of native dystrophin-glycoprotein complex to F-actin binding properties of dystrophin-glycoprotein complex that has been disrupted by various dissociative agents will be determined using the cosedimentation assay to determine whether any other components of the dystrophin-glycoprotein complex modulate the interaction between dystrophin and actin or bind actin independently of dystrophin. Third, the role of the dystrophin- glycoprotein complex in crosslinking F-actin into bundles of networks will be assessed by light scattering and low-g sedimentation assays, as well as by electron microscopy. These experiments will determine whether classification of dystrophin in the actin binding protein family is appropriate. Fourth, this project will use blot overlay and affinity precipitation techniques to determine whether components of the dystrophin-glycoprotein complex interact with other cytoskeletal proteins using. The complementary approaches outlined will yield important new information about the cytoskeletal interactions of dystrophin and its associated proteins. Thus, the proposed research will provide insight into the pathogenesis of Duchenne, Becker and possibly severe autosomal recessive muscular dystrophies through the definition of the function of dystrophin by its interactions with other proteins in normal muscle. The results of this research will also aid in the rational design of fully functional dystrophin mini-genes for use in dystrophin replacement therapies.
| Lindsay, Angus; McCourt, Preston M; Karachunski, Peter et al. (2018) Xanthine oxidase is hyper-active in Duchenne muscular dystrophy. Free Radic Biol Med 129:364-371 |
| Strakova, Jana; Kamdar, Forum; Kulhanek, Debra et al. (2018) Integrative effects of dystrophin loss on metabolic function of the mdx mouse. Sci Rep 8:13624 |
| Le, Shimin; Yu, Miao; Hovan, Ladislav et al. (2018) Dystrophin As a Molecular Shock Absorber. ACS Nano : |
| McCourt, Jackie L; Talsness, Dana M; Lindsay, Angus et al. (2018) Mouse models of two missense mutations in actin-binding domain 1 of dystrophin associated with Duchenne or Becker muscular dystrophy. Hum Mol Genet 27:451-462 |
| Nelson, D'anna M; Lindsay, Angus; Judge, Luke M et al. (2018) Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins. Hum Mol Genet 27:2090-2100 |
| Lindsay, Angus; Schmiechen, Alexandra; Chamberlain, Christopher M et al. (2018) Neopterin/7,8-dihydroneopterin is elevated in Duchenne muscular dystrophy patients and protects mdx skeletal muscle function. Exp Physiol 103:995-1009 |
| Belanto, Joseph J; Olthoff, John T; Mader, Tara L et al. (2016) Independent variability of microtubule perturbations associated with dystrophinopathy. Hum Mol Genet 25:4951-4961 |
| Filareto, Antonio; Rinaldi, Fabrizio; Arpke, Robert W et al. (2015) Pax3-induced expansion enables the genetic correction of dystrophic satellite cells. Skelet Muscle 5:36 |
| McCourt, Jackie L; Rhett, Katrina K; Jaeger, Michele A et al. (2015) In vitro stability of therapeutically relevant, internally truncated dystrophins. Skelet Muscle 5:13 |
| Talsness, Dana M; Belanto, Joseph J; Ervasti, James M (2015) Disease-proportional proteasomal degradation of missense dystrophins. Proc Natl Acad Sci U S A 112:12414-9 |
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