The intersection of lipid metabolism and inflammation in the setting of cardiovascular disease is the overall theme of our PPG. In the revised application we emphasize three specific areas within this major theme that serve as nodal points for the interactions of the component projects; i) Intestine; ii) Lipid Metabolism & Dyslipidemia; and iii) Vascular inflammation. Projects 1, 4 an 5 directly propose specific aims related to the intestine. Projects 1, 2, 4 and 5 propose specific aims related to diet-induced changes in lipid metabolism that result in dyslipidemia, or are directly affected by dyslipidemia. Additionally, Project 3 proposes specific aims related to lipid metabolism in adipose tissue. All five projects propose specific aims related to vascular inflammation. Project 1 (Fogelman) proposes two specific aims.
Aim 1 will determine the mechanisms by which unsaturated lysophosphatidic acid (LPA) and a Western diet (WD) act in the small intestine to cause dyslipidemia and inflammation.
Aim 2 will determine the mechanisms by which transgenic tomatoes expressing an apoA-I mimetic peptide (6F) ameliorates dyslipidemia and inflammation caused by intestinally-derived LPA or WD. Project 2 (Iruela-Arispe) proposes three specific aims.
Aim1 is to identify the mechanism by which pro-atherogenic lipids regulate NOTCH1.
Aim 2 is to determine the role of NOTCH1 in the regulation of barrier stability.
Aim 3 will ascertain the contribution of Notch1 to atherosclerosis using animl models. Project 3 (Bostrom) proposes two specific aims.
Aim 1 will test the hypothesis that the balance between BMP activity and inhibition regulates angiogenesis and adipogenesis in adipose tissue.
Aim 2 will investigate the impact of diabetes, lipid delivery and genetic variation on the balance between BMP activity and inhibition, and adipogenesis and angiogenesis in adipose tissue. Project 4 (Lusis/Edwards) proposes two specific aims.
Aim 1 will use the systems genetics data collected during the present cycle to model interactions in inflammation and atherosclerosis, including the involvement of Notch1, intestinal LPA and Lpcat3.
Aim 2 will test the hypothesis that the transcription factor Zhx2 is required for the survival and proliferatin of macrophage and foam cells in atherosclerotic lesions. Project 5 (Tontonoz) proposes three specific aims.
Aim 1 is to elucidate the role of Lpcat3-dependent phospholipid remodeling in lipid metabolism.
Aim 2 is to determine the role of the LXR-Lpcat3 pathway in inflammation.
Aim 3 is to determine the role of the LXR-Lpcat3 pathway in atherogenesis. Two cores will provide support to the component projects. Core A will provide administrative services. Core B will provide scientific services; analytical chemistry assays, molecular biology related services and morphology related services. The synergy between these specific aims with the support of the cores will result in a novel and comprehensive approach to understanding the intersection of lipid metabolism and inflammation.
Cardiovascular disease remains a major health problem. This Program Project proposes novel approaches to understand fundamental mechanisms that connect the intestine, lipid metabolism and dyslipidemia to vascular inflammation, which leads to heart attack and stroke. Based on the fundamental mechanisms involved this Program also proposes novel approaches to the prevention and treatment of cardiovascular disease.
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