Cytokines play an important role in the pathophysiology of ulcerative colitis and Crohn's disease. As a transcriptional activator of genes encoding inflammatory cytokines, NF-kB may be an important effector molecule in both ulcerative colitis and Crohn's disease and may also be a target for antiinflammatory intervention. In unstimulated cells, NF-kB resides in the cytoplasm in an inactive complex bound to the inhibitor IkB-a. Multiple stimuli, including endotoxin, cytokines, and reactive oxygen intermediates cause release of IkB. NF-kB then enters the nucleus, binds to DNA control elements, and induces transcription. NF-kB activation has been blocked by antioxidants such as vitamin E (vit E) and glutathione (GSH)-enhancing agents, and by anti-inflammatory agents, such as glucocorticoids, mesalamine, and cyclosporine. It is our working hypothesis that NF-kB and NF-kB-inducible cytokines (TNF, IL-1, IL-6, IL- 8) play an etiologic role in the intestinal injury and many of the clinical/biochemical abnormalities observed in ulcerative colitis and Crohn's disease. The overall objectives of this laboratory are to further define mechanisms and modulatory pathways whereby cytokines, such as TNF, IL-1 and IL-8 induce metabolic disturbances and intestinal injury in IBD, with the ultimate goal being development of specific """"""""anticytokine"""""""" therapy for IBD. In this proposal, we will examine the role of NF-kB activation and cytokine production in the intestinal inflammation of IL- 10-deficient (IL-10T) mice, and we will evaluate whether or not inhibition of NF-kB activation attenuates the inflammation. We next will determine whether pharmacological modulation or blockade of NF-kB activation affects cytokine production in lamina propria monocytes and splenic moncytes isolated from IL-10 deficient mice. Finally, we will examine the role of specific transcription factors (NF-kB and NF-IL-6) in the inducible activation of the IL-8 gene in the human intestinal epithelial cell line, Caco-2. These studies should provide new insights into mechanisms of cytokine-mediated injury in intestinal inflammatory states, and this information may assist in development of new forms of therapy for inflammatory bowel disease. I have great enthusiasm and dedication for a career in academic gastroenterology, and a focused research experience in cytokines/molecular biology will greatly enhance my chances of success. Dr. McClain is a highly experienced mentor who has developed a program for Dr. Varilek that will provide the resources, training, and guidance necessary to achieve success.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002401-05
Application #
6176846
Study Section
Special Emphasis Panel (SRC)
Program Officer
Podskalny, Judith M
Project Start
1996-09-30
Project End
2000-12-29
Budget Start
2000-09-01
Budget End
2000-12-29
Support Year
5
Fiscal Year
2000
Total Cost
$107,483
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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