The goal of this project is to improve gene delivery systems that allow inflammation-regulated production of recombinant proteins in vivo. It is based on the premise that if transgene expression is controlled by inflammatory mediators, it should be possible to produce recombinant immunomodulatory proteins in vivo in direct relationship to the onset, intensity and duration of inflammation. The recombinant immunomodulatory protein should then damp, or even prevent altogether, the clinical manifestations of inflammation. As the inflammatory stimulus subsides, production of the immunomodulatory protein will decrease. This negative- feedback approach, which essentially supplements the host's own auto- regulatory control mechanisms, should be very useful for preventing or suppressing inflammatory disease, particularly as it should minimize chronic immunosuppression and other concentration-dependent site effects of the recombinant drug. Potential disease targets include chronic arthritis (rheumatoid, Lyme, reactive [HLA B-27 related, microbially induced], other), organ transplant rejection, other relapsing-remitting inflammatory disorders, and post-trauma immune suppression (hypersusceptibility to infection). Having developed promoter/enhancer elements that allow inflammation- regulated production of recombinant proteins in vivo, and having recently found that this approach can prevent local inflammation in an animal model, we now propose to (1) transfer these regulatory elements into a non-inflammatory vector that will persist for many weeks in vivo, (2) use these new constructs in animal models to define the best way(s) to deliver recombinant proteins to prevent local inflammation or to bolster host defenses after major trauma and (3) combine exogenous (tetracycline) and endogenous (inflammation-regulated) control elements in the same construct, so that gene-based immunomodulatory drug delivery can be tailored to the needs of individual patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038596-08
Application #
6510472
Study Section
Special Emphasis Panel (ZRG1-BM-1 (02))
Program Officer
Korpela, Jukka K
Project Start
1995-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
8
Fiscal Year
2002
Total Cost
$290,920
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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