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Inflammation, innate immunity, TLRs, and atherosclerosis

Institution: Scripps Research Institute
Investigator(s): Peter Tobias, Ph.D.
Award Cycle: 2002 (Cycle 11) Grant #: 11RT-0073 Award: $697,650
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Tobacco smoking, as well as breathing secondhand smoke, causes atherosclerosis. Atherosclerosis is basically an inflammation of the blood vessels. If the inflammation progresses to become very severe it can cause blockage of arteries in the heart or the brain, leading to a heart attack or a stroke. Our studies are aimed at understanding the mechanism of the inflammation as well as understanding recent evidence that suggests that certain microbes can exacerbate atherosclerosis. Recent research on inflammation caused by microbes has identified a family of molecules known as the Toll like receptors (TLRs) and some accessory molecules, a critical one being known as MyD88, that are essential for microbe initiated inflammation. Normally, microbe initiated inflammation is a significant part of the process of attacking and killing microbes. However, in certain instances the syndrome called septic shock can occur and the inflammation can be very damaging, even progressing to death. In this work we will study whether the TLRs and MyD88 that are involved in the inflammatory attack on microbes are also involved in the artery inflammation of atherosclerosis. We will do this in two ways. Using mice that have been bred to be especially susceptible to diet induced atherosclerosis, we will test whether genetic deletion of MyD88, TLR4, or TLR2 protects the mice against atherosclerosis. We will also study the role of TLR4 in human atherosclerosis. There is a form of TLR4 known in humans that does not function as well as the normal form. In a recent study of atherosclerosis in humans known as the Pathobiological Determinants of Atherosclerosis in Youth, tissue samples were taken for further analysis. We will determine which of the individuals in the PDAY study have the non-functional form of TLR4 and attempt to relate it to the severity of atherosclerosis in those individuals through statistics. We expect that the non-functional form of TLR4 will be associated with less severe atherosclerosis. If neither the mouse study nor the human study support our hypothesis that MyD88, TLR4, or TLR2 are involved in the inflammation of atherosclerosis it will suggest that we should look to other mechanisms of inflammation for the roots to the problem in atherosclerosis.
Publications

TLR4 is the signaling but not the lipopolysaccharide uptake receptor.
Periodical: Journal of Immunology Index Medicus:
Authors: Dunzendorfer S, Lee HK, Soldau K, Tobias PS ART
Yr: 2004 Vol: 173 Nbr: 2 Abs: Pg: 1166-1170

Toll-like receptor 4 functions intracellularly in human coronary artery endothelial cells: roles of LBP and sCD14 in mediating LPS responses.
Periodical: FASEB Journal Index Medicus:
Authors: Dunzendorfer S, Lee HK, Soldau K, Tobias PS_x000d_ ART
Yr: 2004 Vol: 10 Nbr: 11 Abs: Pg: 1117-1119

Toll -like receptor 4 functions intracellulary in human coronary artery endothelial cells
Periodical: Roles of LBP and sCD14 in Mediating LPS-responses Index Medicus:
Authors: Dunzendorfer, S, Lee, H. K., Soldau K., Tobias, P.S. ART
Yr: 2004 Vol: 18 Nbr: Abs: Pg: 1117-1119

TLR4 is the signaling but not the lipopolysaccharide uptake receptor.
Periodical: Immunol Index Medicus:
Authors: Dunzendorfer,S., Lee, H.K., Soldau, K., Tobias, P.S. ART
Yr: 2004 Vol: 173 Nbr: Abs: Pg: 1166-70

Flow-dependent regulation of endothelial Toll-like receptor 2 expression through inhibition of SP1 activity
Periodical: Circulation Research Index Medicus:
Authors: Dunzendorfer S., Lee H., K, Tobias, P.S. ART
Yr: 2004 Vol: 95 Nbr: Abs: Pg: 684-91

Modulation of atherosclerosis in mice by Toll -like receptor 2.
Periodical: Clinical Investigation Index Medicus:
Authors: Mullick,A.E., Tobias, P.S., Curtiss, L.K. J. ART
Yr: 2005 Vol: 115 Nbr: Abs: Pg: 3149-59