: Despite recent advances in lifestyles and hypolipidemic therapy, atherosclerosis remains the major cause of morbidity and mortality. Among the many factors that go """"""""beyond cholesterol,"""""""" much evidence supports the oxidation of LDL (OxLDL) as playing a key role in the atherogenic process. While the original interest in OxLDL occurred because it led to rapid macrophage uptake and foam-cell formation, almost 20 years later it is now clear that OxLDL and its many oxidatively modified products contribute to atherogenesis by its proinflammatory, immunogenic and cytotoxic properties, consistent with the concept that atherosclerosis is a chronic inflammatory process that involves complex interactions between the endogenous cells of the artery and cells recruited from the blood, chiefly monocytes and T cells. The goal of the La Jolla SCOR is to investigate mechanisms by which oxidation influences these processes and specifically focuses on the role of monocyte/macrophages and the role of T cells and immune responses. Because the recruitment of monocytes into the artery is rate limiting, we will study the extracellular and intracellular mechanisms for the regulation of chemokine receptors and adhesion molecules which determine rates of recruitment and retention. We will utilize new methods to quantify the rates of recruitment of monocytes into lesions and the impact of various interventions, such as such as deletion of CCR2, or MCP-1, or the use of vitamin E or agonists for PPARgamma. We will study the structure and function of receptors involved in the binding and internalization of OxLDL, including CD36, and CD68, and define ligands on OxLDL and apoptotic cells for these receptors. Nuclear receptors such as PPARs, LXRs and possibly ESRs appear to play pivotal roles in expression of genes known to affect atherogenesis, such as scavenger receptors, cytokines, and cholesterol homeostasis. We will determine the molecular mechanisms by which activation of these receptors modulate macrophage gene expression, and determine the role of each receptor in vivo in inflammation and atherosclerosis models through the use of novel gene targeted murine models. Oxidation of LDL renders it immunogenic and we will determine the consequences to atherogenesis of the immune response. In particular, we will determine the mechanisms by which immunization of mice with OxLDL ameliorates atherosclerosis and specifically determine the role of T cells in this process. We will utilize immunological techniques to measure the relative rates of oxidation of LDL in vivo in animals and determine the impact of various interventions, such as vitamin E. Finally, we will determine the epidemiologic relationship of various plasma markers of OxLDL, including a measure of OxLDL (mmLDL) itself, with respect to clinical and morphological measures of atherosclerosis and the ability of these measures to predict disease. In summary, the La Jolla SCOR proposes a multi-disciplinary approach that focus on the consequences to atherogenesis of the immune response to OxLDL and on the effects of OxLDL on monocyte/macrophage biology. These insights may lead to novel approaches to the treatment and prevention of atherosclerosis.
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