Severe sepsis is a clinical syndrome occurring in patients with severe injury or infection, with an annual incidence of approximately 750,000 cases in the United States. The mortality rate is 20-30%, and currently there are no specific therapeutic agents approved for clinical use. Indeed, the only specifically approved agent (Xigris) was recently withdrawn from the clinic because of poor efficacy. Autopsy studies have shown that the major cell death mechanism in severe sepsis victims is via programmed cell death through two major pathways, termed "apoptosis" and "pyroptosis." Prior efforts to prevent cell death by blocking the inflammasome had been extremely difficult, because until recently, the identity of a major regulatory protein that controls the inflammasome was unknown. However, an innovative discovery has now revealed the identity of the key regulatory protein that is required for activation of the inflammasome: it is a kinase termed "PKR." We have reported this discovery in Nature, and it now enables us to directly target the inflammasome by inhibiting PKR;this also prevents programmed cell death. The objective of this proposal is to study the role of these PKR pathways in the pathogenesis of sepsis. We will use an innovative new approach to focus on the overall hypothesis that pyroptosis during severe sepsis is deleterious, and that inhibiting pyroptosis by inactivating PKR-dependent inflammasome activation will be beneficial to the host. This will be accomplished in three Aims:
Specific Aim 1. Role of PKR as an essential regulator of pyroptosis;
Specific Aim 2. Role of PKR in inflammasome assembly;
and Specific Aim 3. PKR as a therapeutic target in sepsis. The results of this innovative approach should reveal the mechanisms of cell death in severe sepsis, and open a pathway to preventing it with agents that inhibit PKR.

Public Health Relevance

Severe sepsis is a major public health problem, because it is the leading cause of death in hospitalized patients in the United States, and one of the ten leading causes of death in the developed world. The studies proposed here will provide significant data that can be used to develop therapeutic modalities for the prevention and treatment of sepsis/septic shock.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM106314-01
Application #
8496322
Study Section
Special Emphasis Panel (ZRG1-SBIB-X (02))
Program Officer
Dunsmore, Sarah
Project Start
2014-09-15
Project End
2018-07-31
Budget Start
2014-09-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$320,150
Indirect Cost
$130,150
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030