Sepsis is a life-threatening disease with high morbidity and mortality. New therapeutic strategies are urgently needed to treat this devastating disease. Uncontrolled endothelial inflammatory responses, which often leads to inflammatory vascular injury, contribute to the pathogenesis of multiple organ failure in sepsis. HDAC6, a histone deacetylase, has been reported to modulate nuclear and non-nuclear protein function through deacetylation. In this project, we will investigate HDAC6 regulation of endothelial inflammatory injury during sepsis. In our preliminary studies, we demonstrated that HDAC6 knockdown or selective HDAC6 inhibition prevented TNF-? induced endothelial ICAM-1 expression, which was associated with increased ?-tubulin acetylation and reduced STAT1 activation. Furthermore, in mouse models of sepsis, HDAC6 inhibition blocked sepsis-induced lung ICAM-1 expression, induced ?-tubulin acetylation, and suppressed STAT1 activation in lung tissues, which was associated with reduced lung inflammatory injury and increased survival rate. In the proposed studies, we will conduct a serial of experiments to assess the role of HDAC6 in sepsis-induced endothelial inflammatory responses, and to investigate therapeutic mechanisms of HDAC6 inhibition against endothelial inflammatory signaling in sepsis.

Public Health Relevance

Successful completion of the proposed studies will reveal a novel role of HDAC6 in sepsis-induced endothelial inflammatory signaling. The studies will validate the therapeutic potential of HDAC6 inhibition against inflammatory vascular injury in sepsis. The proposed studies will provide important information for future clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL137910-01A1
Application #
9593958
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Sarkar, Rita
Project Start
2018-06-15
Project End
2022-04-30
Budget Start
2018-06-15
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526