Muscle wasting during sepsis and after injury is at least in part mediated by glucocorticoids and mainly reflects ubiquitin-proteasome-dependent protein breakdown. Recent studies suggest that the gene expression of the newly discovered ubiquitin-ligase atrogin-1 is upregulated in atrophying muscle by glucocorticoids. Other studies suggest that the expression and activity of the transcription factors C/EBP Beta and delta are increased but it is not known if C/EBP-Beta and delta regulate the atrogin-I gene in muscle wasting. The role of the nuclear cofactor p300 for gene regulation in atrophying muscle is also unknown. In the proposed project, I will test the hypotheses that a) glucocorticoids activate the atrogin-1 gene secondary to increased expression and activity of C/EBP and p300; and b) glucocorticoid-induced C/EBP-atrogin-1 gene activation cascade is at least in part responsible for muscle wasting. The project is important because it will further define the molecular regulation of glucocorticoid-related muscle wasting, such as seen in sepsis and after severe injury. The use of cultured muscle cells will allow for defining mechanisms of muscle wasting at the gene level.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK066964-01
Application #
6740701
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Hyde, James F
Project Start
2003-12-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$50,548
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215