Inflammatory processes are characterized by tissue- targeted accumulations of lymphocytes and the local elaboration of adhesion molecules, growth factors, proteases and cytokines. These processes originate in response to infectious agents and tissue trauma. Diseases such as rheumatoid arthritis, atherosclerosis, pulmonary fibrosis and Crohn's disease are examples of deleterious inflammation. Understanding the pivotal relationships in cell biology which control protection versus chronic damage is critical for preventing disease and treating millions of individuals with such diseases. Here, we study atherosclerosis as a model for inflammation. ? ? The long range goal is to understand how tumor necrosis factor alpha (TNF) receptors and ligands, TNF and lymphotoxin (LTa) contribute to atherosclerosis. Although studies implicate TNF as playing a deleterious role in atherosclerosis, our data suggests that its contribution is more complicated and dependent upon stage of atherosclerosis and cell types involved. In addition, we are the first group to show that LTa is present at the artery wall and loss of LTa also influences the progression of atherosclerosis. We are using mice deficient and transgenic in TNF ligands or receptors to demonstrate how these molecules contribute to atherogenesis and atheroprogression in three specific aims: (1) determine the role of TNF in cholesterol homeostasis in macrophages, (2) determine whether pharmaceutical inhibition or induced gene expression of TNF or LTa results in improvement in atherosclerosis severity, (3) determine the relative contribution of TNF family members derived from the hematopoietic compartment versus the fixed tissue compartment in atherosclerosis. ? ? Overall, this work will provide new and detailed information about the relative contributions of TNF molecules to atherosclerosis. We believe that detailed knowledge is still needed in the TNF field to realize the important goal of developing therapies which harness anti-atherogenic functions of TNF. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079382-02
Application #
7232006
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wassef, Momtaz K
Project Start
2006-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$402,965
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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