The common thread for all muscular dystrophies is progressive muscle weakness and degeneration. Regardless of the underlying cause, all people who suffer from this group of diseases can benefit from agents which improve muscle strength and enhance regenerative capacity. The goals of this grant are to identify the best IGF-I isoform to counter weakness and degeneration common to all muscular dystrophies and to develop new strength-promoting therapies based on the endogenously expressed E peptides. To achieve these goals, directed expression of three different IGF-I isoforms will be utilized in two different animals models for muscular dystrophy, and the effects on muscle function, mass, and stabilization will be examined as outcome measures for efficacy. Second, to exclude potentially harmful agents, the effects of IGF-I on the hearts will be examined, and tumorigenicity will be evaluated in the Tg-rasH2 mouse. Next, in vitro studies will be utilized to carefully examine the therapeutic potential of the E-peptide extensions produced by the IGF-I isoforms. The dual approach of in vivo and in vitro experiments will accelerate the identification of novel peptides and help to optimize the IGF-I isoform to counter the common pathologies associated with muscular dystrophy. Relevance: The muscular dystrophies have no established cure, and although the diseases has many different causes, all patients suffer from muscle weakness and fragility. Therefore, there is a significant need to maintain or at least slow the progression of muscle wasting to buy time for an effective therapy to be developed. Growth promoting strategies are one way to combat this loss of muscle strength, and can provide benefit to all people suffering from these muscle diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR056480-02
Application #
7575778
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Nuckolls, Glen H
Project Start
2008-02-26
Project End
2010-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
2
Fiscal Year
2009
Total Cost
$173,250
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Brisson, Becky K; Barton, Elisabeth R (2012) Insulin-like growth factor-I E-peptide activity is dependent on the IGF-I receptor. PLoS One 7:e45588
Barton, Elisabeth R; DeMeo, J; Lei, Hanqin (2010) The insulin-like growth factor (IGF)-I E-peptides are required for isoform-specific gene expression and muscle hypertrophy after local IGF-I production. J Appl Physiol 108:1069-76
Ostrovsky, Olga; Eletto, Davide; Makarewich, Catherine et al. (2010) Glucose regulated protein 94 is required for muscle differentiation through its control of the autocrine production of insulin-like growth factors. Biochim Biophys Acta 1803:333-41
Pfeffer, Lindsay A; Brisson, Becky K; Lei, Hanqin et al. (2009) The insulin-like growth factor (IGF)-I E-peptides modulate cell entry of the mature IGF-I protein. Mol Biol Cell 20:3810-7