Muscular dystrophy refers to a diverse group of debilitating hereditary muscle disorders typified by a host of symptoms, including progressive muscular weakness and muscle wasting. To examine the molecular mechanisms that contribute to muscle loss, we have established a potent model of muscle degeneration in Drosophila. Constitutive expression of the ecdysone receptor (EcR) in somatic muscles of Drosophila larvae triggers their degeneration, thereby serving as a model for elucidating the molecular underpinnings of muscle atrophy/degeneration in a genetically tractable organism. Using this Drosophila system, we propose the following:
Aim 1. Establish the relative contribution of catabolic and anabolic signals to EcR-mediated muscle wasting: Using a combination of genetic and biochemical techniques, we will examine the effect of inhibiting apoptosis, autophagy and degradation via the proteasomal pathway (i.e catabolic signals) as well as hyperstimulation of the insulin signaling network (anabolic signals) on EcR-mediated muscle degeneration;
Aim 2. Identify universal biomarkers of muscle degeneration in flies and generate a """"""""muscle degeneration reporter"""""""" for subsequent genetic screens: We will compare the mRNA and proteomic expression profiles of EcR-mediated muscle degeneration with that of three other well-established fly models of muscle degeneration (i.e. the dystrophin model, parkin/pinkl model and a sporadic inclusion-body myositis model) to identify several muscle pan-degeneration markers. Finally, we will develop a suitable assay for muscle degeneration, most likely a Luciferase transcriptional reporter based on one of the pan-degeneration markers;
and Aim 3. Identify drug targets via a transgenic RNAi screen in muscles to identify suppressors of EcR- mediated muscle degeneration: Using publicly available RNAi transgenic lines, we will carry out a genome- wide in vivo RNAi screen (using the Luciferase-based reporter developed in Aim 2) in larval muscles to identify genes/pathways whose inhibition can ameliorate EcR-mediated muscle degeneration.

Public Health Relevance

Given the high degree of conservation between the Drosophila and human genomes, we anticipate that molecular targets identified by this study will eventually provide leads for addressing muscle wasting/degeneration in humans. In summary, we seek to provide a genome-wide portrait of the molecular mechanisms that either trigger or suppress ecdysone-mediated muscle wasting in Drosophila, with the ultimate goal of identifying suitable drug targets for attenuating muscle degeneration in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AR057291-02
Application #
7800296
Study Section
Special Emphasis Panel (ZRG1-F10-H (20))
Program Officer
Boyce, Amanda T
Project Start
2009-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$52,154
Indirect Cost
Name
Harvard University
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Owusu-Ansah, Edward; Song, Wei; Perrimon, Norbert (2013) Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155:699-712
Owusu-Ansah, Edward; Banerjee, Utpal (2009) Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461:537-41