Persistent and exaggerated chronic inflammation that remains unresolved is linked to tissue destruction and cardiovascular disease, which remains the leading cause of death in developed countries. Therefore timely termination of inflammatory responses is crucial to prevent detrimental effects. Activation of the nuclear factor kappaB (NF-?B) is essential for the inflammatory activation of endothelial cells and the subsequent recruitment and transmigration of circulating leukocytes by adhesion molecules. However, the molecular mechanisms that terminate endothelial cell activation are still not completely understood. We identified a novel PYRIN domain-only protein (POP) involved in the resolution of inflammatory activation of endothelial cells by blocking cytokine and IFI16-mediated NF-?B activity and inflammatory mediator synthesis. We propose to elucidate the responsible molecular mechanism and the consequences on endothelial cell activation and leukocyte adhesion and transmigration. In the first specific aim, we will establish POP3 as a negative regulator of the activation of endothelial cells and inflammatory mediators.
In specific aim 2, we will determine the impact of POP3 on leukocyte-endothelial cell adhesion and transmigration.
In specific aim 3, we propose to study the in vivo role of POP by generating a novel mouse model expressing POP from the Tie2 promoter specifically in endothelial cells and to evaluate POP peptidomimetics in the resolution of endothelial cell activation. POPs are negative regulators of macrophage inflammasomes, while this novel POP is the first POP identified to terminate inflammatory responses in endothelial cells. It is important to understand the ramifications of this novel mechanism on the resolution of endothelial cell activation for the treatment of cardiovascular disease.

Public Health Relevance

Cardiovascular disease is the leading cause of morbidity and mortality in the US. A major factor in the onset and progression of cardiovascular disease is chronic inflammation and persistent activation of endothelial cells via the transcription factor NF-?B, and inhibition of NF-?B is thus considered a promising therapeutic target to combat cardiovascular disease. Timely resolution of inflammatory reactions is essential to prevent detrimental effects, but the molecular mechanisms that terminate endothelial cell activation are poorly understood. We identified a novel mechanism responsible for terminating cytokine-mediated NF-?B activation, and therefore delineating this protective event will have significant ramifications for designing novel and improved therapies to combat endothelial cells activation and cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL097183-01A1
Application #
7995154
Study Section
Special Emphasis Panel (ZRG1-VH-F (90))
Program Officer
Gao, Yunling
Project Start
2010-07-15
Project End
2012-06-30
Budget Start
2010-07-15
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$228,750
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
de Almeida, Lucia; Khare, Sonal; Misharin, Alexander V et al. (2015) The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease. Immunity 43:264-76
Khare, Sonal; Ratsimandresy, Rojo A; de Almeida, LĂșcia et al. (2014) The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses. Nat Immunol 15:343-53
Radian, Alexander D; de Almeida, Lucia; Dorfleutner, Andrea et al. (2013) NLRP7 and related inflammasome activating pattern recognition receptors and their function in host defense and disease. Microbes Infect 15:630-9
Ratsimandresy, Rojo A; Dorfleutner, Andrea; Stehlik, Christian (2013) An Update on PYRIN Domain-Containing Pattern Recognition Receptors: From Immunity to Pathology. Front Immunol 4:440
Khare, Sonal; Luc, Nancy; Dorfleutner, Andrea et al. (2010) Inflammasomes and their activation. Crit Rev Immunol 30:463-87