This is a competitive renewal following an initial Shannon award for a project investigating the role of apoptosis (programmed cell death, PCD) as a molecular mechanism in the multiple organ dysfunction syndrome (KODS). MODS remains the leading cause of death in surgical intensive care units. The central hypothesis is that the vascular endothelial and gut epithelial injuries which are characteristic of MODS are in part the consequence of premature activation of PCD. This activation appears to be the consequence of unexpected adverse interaction between otherwise salutary programs of stress gene expression.
The aims of this application focus on the intra cellular mechanism which is activated during shock/resuscitation and culminates in PCD. Using molecular biology as well as more classical cell biology tools, we propose to confirm or exclude specific oxidant/antioxidant mechanisms; identify explicit roles for gene products which regulate this untimely PCD; and thereby develop the basis for new therapeutic strategies in MODS. Cultured cells as well as rats will be used to model clinical events which precipitate MODS. Cultured cells will be manipulated using gene transfection and also antisense techniques to test the contribution of specific gene products to the redox state and to the regulation of PCD. Rats will undergo hemorrhagic shock/resuscitation and heat shock to test the ability of these stresses, in the presence or absence of specific drugs, to modulate the rate at which intestinal epithelium executes apoptosis. Both systems will be manipulated and assayed with respect to antioxidants. Preliminary data suggests that the central hypothesis is correct and moreover points to an unexpected link between MODS and oncogenesis as pathologically (but oppositely) dysregulated extremes of the same physiologic process: apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM048095-02
Application #
2185537
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1992-09-30
Project End
1998-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130