The goal is to define mechanisms leading to the development and progression of chlamydiae-mediated atherosclerosis. Approaches will center on studying signaling mechanisms for cLPS and cHsp60, effector molecules known to activate host pro-inflammatory pathways. The hypothesis to be investigated is that cLPS and cHsp60 utilize the Toll-like Receptor-4 (TLR-4) to activate macrophages and endothelial cells via NF-kB and MAPK through myeloid differentiation protein (MyD88). The effects of this activation will lead to increased expression of pro-inflammatory cytokines (IL-6, IL-8), adhesion molecules (ICAM-1 VCAM-1), growth factors (M-CSF), cyclooxygenase-2 (Cox-2) and enhanced transendothelial cell migration of monocytes; all factors implicated in atherogenesis. The hypothesis also will be tested in vivo by determining if apo-E-/-, TLR-4-/- double knockout mice remain indifferent to C. pneumoniae-induced accelerated lesion progression.
The specific aims are to (1) determine if TLR-4 is the signaling receptor for cLPS and cHsp60 and to investigate the signaling pathways induced (ERK1/ERK2, p38MAPK and JNK) and other down-stream events leading to NK-kB activation; (2) to define the molecular mechanisms involved in cLPS and cHsp60-induced transendothelial cell migration of monocytes; and (3) to create double knockout mutants in mice (TLR4-/-, apoE-/- and MtD88-/-, apoE -/-) to investigate the contributions of TLR-4 and MyD88 in the initiation and progression of atherosclerosis in the presence and absence of C. pneumoniae infection. The results of these studies are expected to lead to new targets for intervention and prevention of coronary atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL066436-01
Application #
6258167
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Tolunay, Eser
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$363,950
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Tumurkhuu, Gantsetseg; Dagvadorj, Jargalsaikhan; Porritt, Rebecca A et al. (2018) Chlamydia pneumoniae Hijacks a Host Autoregulatory IL-1? Loop to Drive Foam Cell Formation and Accelerate Atherosclerosis. Cell Metab 28:432-448.e4
Chen, Shuang; Shimada, Kenichi; Crother, Timothy R et al. (2018) Chlamydia and Lipids Engage a Common Signaling Pathway That Promotes Atherogenesis. J Am Coll Cardiol 71:1553-1570
Tumurkhuu, Gantsetseg; Shimada, Kenichi; Dagvadorj, Jargalsaikhan et al. (2016) Ogg1-Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis. Circ Res 119:e76-90
Sorrentino, Rosalinda; Yilmaz, Atilla; Schubert, Katja et al. (2015) A single infection with Chlamydia pneumoniae is sufficient to exacerbate atherosclerosis in ApoE deficient mice. Cell Immunol 294:25-32
Jones, Heather D; Crother, Timothy R; Gonzalez-Villalobos, Romer A et al. (2014) The NLRP3 inflammasome is required for the development of hypoxemia in LPS/mechanical ventilation acute lung injury. Am J Respir Cell Mol Biol 50:270-80
Jupelli, Madhulika; Shimada, Kenichi; Chiba, Norika et al. (2013) Chlamydia pneumoniae infection in mice induces chronic lung inflammation, iBALT formation, and fibrosis. PLoS One 8:e77447
Fukata, M; Arditi, M (2013) The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol 6:451-63
Chen, Shuang; Lee, Youngho; Crother, Timothy R et al. (2012) Marked acceleration of atherosclerosis after Lactobacillus casei-induced coronary arteritis in a mouse model of Kawasaki disease. Arterioscler Thromb Vasc Biol 32:e60-71
Shimada, Kenichi; Crother, Timothy R; Karlin, Justin et al. (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401-14
Crother, Timothy R; Ma, Jun; Jupelli, Madhulika et al. (2012) Plasmacytoid dendritic cells play a role for effective innate immune responses during Chlamydia pneumoniae infection in mice. PLoS One 7:e48655

Showing the most recent 10 out of 49 publications