A critical step in inciting intestinal inflammation is the elaboration of proinflammatory factors such as TNF. TNF activates NF-kappa-B and JNK signaling pathways, which induce the expression of other genes in a pro-inflammatory cascade. While it is clear that dysregulated expression of TNF can cause intestinal inflammation, it is not clear how TNF signals are normally down-regulated or controlled in vivo. To better understand the molecular mechanisms by which TNF signals are regulated, the investigator is studying A20, a novel molecule thought to regulate cellular responses to TNF. The PI has generated A20 deficient (A20-/-) mice and these mice develop spontaneous bowel inflammation, which is dramatically worsened after exposure to TNF. These remarkable physiological problems are associated with molecular defects in regulating TNF induced NF-kappa-B activity and cellular resistance to programmed cell death (PCD). This compelling preliminary data highlights A20's pivotal role in terminating TNF responses in vivo. It also provides a unique opportunity to interrogate the molecular mechanisms by which such control is normally achieved. Thus, the investigator proposes to: (1) delineate the role of A20 in regulating both spontaneous and TNF induced intestinal inflammation; (2) determine both the requirement and the contribution of A20-/-lymphocytes to mediating intestinal activation in these mice; (3) define the relative contributions of nonlymphoid (myeloid) hematopoietic cells versus non-hematopoietic cells; and (4) define the role of A20 in regulating TNF induced NF-kappa-B and PCD responses in intestinal tissue. Understanding both the cellular and molecular mechanisms by which A20 regulates TNF responses will provide unique insights into how TNF induced inflammation is normally terminated, and may also lead to novel therapies for human IBD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052751-09
Application #
6935373
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
1996-09-30
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2007-05-31
Support Year
9
Fiscal Year
2005
Total Cost
$305,854
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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