This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Acute kidney injury (AKI) is a common and debilitating condition with few therapeutic options. Inflammation is a main cause of tissue injury following an acute insult such as ischemia. Superimposed on this, a regenerative response is mounted shortly after the inflammatory injury. Long term outcome is determined by the balance between these two processes, with experimental AKI either resulting in return to normal tissue structure or tissue fibrosis. Immediately following injury, TNFa levels are elevated causing apoptosis of proximal tubule epithelial cells, recruitment of inflammatory cells and widespread tissue damage. TNFa is released by both kidney epithelia and macrophages, and signals directly to kidney epithelia through all phases of injury, including resolution. The vigorous regenerative response seen in the resolution phase depends on BMP and Wnt signaling. TNFa, BMP and Wnt all signal directly to the renal epithelial cell, and we hypothesize that the integrated response to these factors determines the switch from tissue destruction to repair. Map3k7 (TAK) is a common component of TNFa, BMP and canonical Wnt signaling pathways. We propose that this kinase integrates inflammatory and regenerative signaling within the renal epithelial cell, determining the balance between tissue destruction and repair. To test this concept we will: i) Define the role of Map3k7 in balancing the integrated outcome of TNFa, BMP and Wnt signaling in primary human and mouse proximal tubule epithelial cells, ii) Test the requirement for Map3k7 in determining the switch between proximal tubule destruction and regeneration in mouse models of AKI.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR018789-09
Application #
8360270
Study Section
Special Emphasis Panel (ZRR1-RI-6 (01))
Project Start
2011-06-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
9
Fiscal Year
2011
Total Cost
$181,479
Indirect Cost
Name
Maine Medical Center
Department
Type
DUNS #
071732663
City
Portland
State
ME
Country
United States
Zip Code
04102
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