The anemia, neutropenia, loss of lean body mass and mortality of AIDS patients with wasting are associated with elevated levels of the proinflammatory cytokines TNFalpha and IL-1beta. AIDS patients with wasting are often given a 12- week therapy with very high doses of recombinant human growth hormone to increase plasma IGF-I, lean muscle mass and quality of life. However, the responsiveness of both hematopoietic and muscle cells to IGF-I has been documented to be defective in these patients. The central hypothesis of this application is that TNFalpha and IL-lbeta are responsible for inducing a state of IGF-I receptor resistance, which contributes to not only muscle wasting but also to the anemia and neutropenia of AIDS. IGF-I targets both hematopoietic myeloid progenitor cells and muscle myoblasts, and here we hypothesize that the molecular mechanism for IGF-I receptor resistance in wasting AIDS patients is caused by proinflammatory cytokines. Objective 1 will test the idea that IGF-I promotes promyeloid cell survival by blocking activation of the caspase family of serine proteases and whether this is inhibited by TNFa. Objective 2 focuses on the survival promoting activity of the tyrosine phosphorylated IGF-I receptor, including insulin-receptor substrate- 1 (IRS-1), IRS-2, PI 3-kinase and Akt. Objective 3 will determine if proinflammatory cytokines inhibit key IGF-I proliferative signals, including Shc, EFK1/2, AFX forkhead transcription factors and the cyclin-dependent kinase inhibitor 27. Finally, objective 4 will extend these results with myeloid progenitor cells to muscle myoblasts. Preliminary results indicate that low blood concentrations of TNFalpha and IL-1beta found in wasting AIDS patients inhibit the ability of IGF-I to promote both protein synthesis and differentiation into myotubes. This objective will also test the new idea that ceramide, a mediator of the actions of both TNFalpha and IL-1beta, induces resistance of the IGF-I receptor in muscle myoblasts. These studies are needed to understand how clinically-relevant concentrations of proinflammatory cytokines in wasting AIDS patients impair the functional ability of a major hormone receptor on both immune and muscle myoblast cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050442-03
Application #
6789383
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Bridges, Sandra H
Project Start
2002-09-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$338,765
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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