The long-term goal of our research is to investigate how the intracellular signaling circuitry is wired in response to specific extracellular stimuli, thereby identifying potential therapeutic targets for prevention and treatment of human diseases. In this proposal, we will study the molecular mechanism underlying the IKK signaling network and its pathophysiological implications, using regulation of Bad by IKK in TNF?-induced apoptosis as a molecular probe. Using multifaceted approaches, we uncovered a second signaling pathway of the IKK signaling network, i.e., the IKK-Bad axis. We found that Bad is a novel target of IKK and is also required for TNF?-induced apoptosis in vitro and in vivo. Regulation of Bad by IKK is involved in inhibition of TNF?-induced apoptosis. We hypothesize that in addition to activation of NF-?B, IKK inhibits TNF?-induced apoptosis via inactivation of Bad, i.e., the "NF-?B activation and Bad inactivation" model. This proposal is novel, as it will study the role of the IKK-Bad axis in apoptosis induced by TNF? and other death stimuli, as well as in necrosis and autophagy, and the underlying mechanism and pathophysiological functions of the regulation in vitro and in vivo. This study will put forward a novel paradigm regarding the IKK signaling network and will provide a better understanding of the biological functions of the IKK signaling network in terms of regulation of cell death, which plays an important role in many human diseases.

Public Health Relevance

The I?B kinase complex (IKK) is activated by a variety of extracellular stimuli; including the pro-inflammatory cytokine tumor necrosis factor (TNF ); and in turn it regulates immune responses; inflammation and cell death. The biological functions of IKK are thought to be mediated by NF-?B. Our finding that IKK inhibits TNF -induced apoptosis through inactivation of the pro-death Bcl-2 family protein Bad uncovers a second signaling pathway of IKK signaling network; i.e.; the IKK-Bad axis; and should shed light on our understanding of molecular mechanism underlying cell death; which deregulation leads to numerous human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM103868-02
Application #
8670762
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Gaillard, Shawn R
Project Start
2013-06-07
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$300,200
Indirect Cost
$110,200
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637