Muscular dystrophy is a genetic disease for which there is no cure. One of the most severe forms of muscular dystrophy is Duchenne Muscular Dystrophy (DMD). DMD and a subset of the limb girdle muscular dystrophies have in common disruption of the dystrophin protein complex. Disrupting the dystrophin complex lead to a fragile muscle membrane, loss of myofibers and replacement of the muscle with fibrosis or scarring. Multiple lines of evidence point to fibrosis is as a driver of muscular dystrophy pathology. We hypothesize that fibrosis provides a scaffold that promotes an unfavorable cytokine profile that further damages muscle. We further hypothesize that the primary components of the unfavorable cytokine profile are TGFp and the related TGFp family member myostatin. Together, TGFp and myostatin, lead to increased fibrosis, reduced muscle mass and regeneration, and aggravated membrane fragility. Therefore, we propose to determine the means by which TGFp and myostatin are normally sequestered by the matrix and held unavailable for receptor engagement and signaling and to determine how to promote inactivation of TGFp and myostatin in muscular dystrophy (Project 1). We will also demonstrate necessary proteolytic cleavage steps for release and processing of myostatin, and related molecules, and the degree to which soluble receptors can be effective in treating muscular dystrophy (Project 2). We will also sequentially assess the distinct intracellular signaling pathways that are triggered by TGFp and myostatin and test whether inhibiting these pathways improves muscle function and pathology in muscular dystrophy (Project 3). Three established investigators (McNally, Lee, and Molkentin) will lead these projects forming a distinctive team where their combined expertise will define the TGFp/myostatin pathway for therapeutic intent in muscular dystrophy. Three Cores will support the Projects;Core A will integrate the efforts at our three institutions to assure seamless collaboration and transfer of materials. Core B will provide histopathological assessment of muscular dystrophy after genetic manipulation and treatments, and Core C will perform functional analysis in vivo and provide support to Core B.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS072027-04
Application #
8685343
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Nuckolls, Glen H
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60637
Quattrocelli, Mattia; McNally, Elizabeth M (2016) BMP and WNT: the road to cardiomyocytes is paved with precise modulation. Stem Cell Investig 3:21
Lamar, Kay-Marie; Bogdanovich, Sasha; Gardner, Brandon B et al. (2016) Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ. PLoS Genet 12:e1006019
McNally, Elizabeth M (2016) Questions and Answers About Myostatin, GDF11, and the Aging Heart. Circ Res 118:6-8
Tjondrokoesoemo, Andoria; Schips, Tobias; Kanisicak, Onur et al. (2016) Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice. Hum Mol Genet 25:1192-202
Lamar, Kay-Marie; Miller, Tamari; Dellefave-Castillo, Lisa et al. (2016) Genotype-Specific Interaction of Latent TGFβ Binding Protein 4 with TGFβ. PLoS One 11:e0150358
Demonbreun, Alexis R; Allen, Madison V; Warner, James L et al. (2016) Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption. Am J Pathol 186:1610-22
Demonbreun, Alexis R; McNally, Elizabeth M (2016) Plasma Membrane Repair in Health and Disease. Curr Top Membr 77:67-96
Tjondrokoesoemo, Andoria; Schips, Tobias G; Sargent, Michelle A et al. (2016) Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice. J Biol Chem 291:9920-8
Gardner, Brandon B; Swaggart, Kayleigh A; Kim, Gene et al. (2015) Cardiac function in muscular dystrophy associates with abdominal muscle pathology. J Neuromuscul Dis 2:39-49
Burr, A R; Molkentin, J D (2015) Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy. Cell Death Differ 22:1402-12

Showing the most recent 10 out of 60 publications