This K99/R00 will support candidate's career goal to become a researcher in the area of cardiovascular disease with a focus on atherosclerosis. The candidate has past educational background related with cell biology and pharmacology mainly on receptor signaling projects, and simple array analysis. The candidate is currently a postdoctoral fellow at UCLA and the K99 training will be executed under mentor Dr. Judith A. Berliner and co-mentor Dr. Aldons J. Lusis at UCLA. The university system is well equipped with highly productive and supportive research facilities including systemized training of conduct of research. The university administrative system is very supportive for the success of new investigators. Dr. Berliner is a pioneering researcher who identified important roles of oxidized phospholipids in the vascular inflammatory responses. Her experience with analysis of immuno-histochemistry will be important to the success of the proposed studies. Dr. Lusis is an outstanding researcher in the field of systems genetics whose work has been important in identifying genetic factors and novel signaling pathways controlling the development of atherosclerosis. During this K99 training phase, the candidate will meet frequently with mentor and co-mentor. The candidate will also meet with advisory board committee every 6 months. During the K99 mentoring phase, the candidate will focus on mastering immuno-histochemistry and lesion analysis methods, which is one of big advantages of current lab and associated Core labs. Another important aspect of the K99 will be learning the analytical tools to do analyze high-throughput transcript and genotyping datasets;these studies are being performed by a large number of those in the Lusis group. During the independent R00 phase, the candidate will mainly focus on the in-depth mechanistic studies for MP activation by Ox-PAPC in the endothelial cells, and the validation study of the significance of the genetic factors and cellular pathways identified via systems genetics approach. The main goal of this proposed study is to define proximal events in oxidized phospholipid (Ox-PAPC) activation of this inflammatory pathway. In this study in Aim 1, candidate will identify the mechanism by which Ox-PAPC induces activation of the MPs using in vitro culture of endothelial cells.
In Aim 2, candidate will determine if this pathway is activated for inflammation and lesion formation in mouse model of atherosclerosis. Finally, in Aim 3, a systems genetics approach will be used to identify genetic factors and novel pathways controlling proximal inflammatory responses in vascular endothelium. For this study the candidate will use transcript and genotyping data sets of the aortic endothelial cells isolated from 96 human donors which datasets and cells are currently available. The K99 training phase under mentor and co-mentor in the current lab clearly fill the technical gaps to execute the projects proposed. After the training phase, the candidate will be equipped with more diverse tools and approaches to study the cardiovascular disease for successful transit to the independent R00 phase.
This study is to find preventive and therapeutic targets for the chronic vascular inflammatory diseases like atherosclerosis. The primary aim is to contribute to the development of reagents targeting critical step of vascular inflammation to increase life expectancy of human population, especially for aged people. Oxidative stress and the oxidation products of lipids have been shown to be involved in the development of cardiovascular diseases. This study will test the hypothesis that the oxidized phospholipids produced by vascular oxidative stress will activate metalloproteinases on the endothelial cell surface for proinflammatory cytokine expression leading to chronic inflammatory conditions in the vessel. These studies also have the potential to identify additional therapeutic targets and identify genetic factors that increase susceptibility of atherosclerosis.
|Zhong, Wei; Springstead, James R; Al-Mubarak, Ramea et al. (2013) An epoxyisoprostane is a major regulator of endothelial cell function. J Med Chem 56:8521-32|
|Lee, Sangderk; Springstead, James R; Parks, Brian W et al. (2012) Metalloproteinase processing of HBEGF is a proximal event in the response of human aortic endothelial cells to oxidized phospholipids. Arterioscler Thromb Vasc Biol 32:1246-54|
|Lee, Sangderk; Birukov, Konstantin G; Romanoski, Casey E et al. (2012) Role of phospholipid oxidation products in atherosclerosis. Circ Res 111:778-99|
|Birukova, Anna A; Lee, Sangderk; Starosta, Vitaliy et al. (2012) A role for VEGFR2 activation in endothelial responses caused by barrier disruptive OxPAPC concentrations. PLoS One 7:e30957|
|Springstead, James R; Gugiu, B Gabriel; Lee, Sangderk et al. (2012) Evidence for the importance of OxPAPC interaction with cysteines in regulating endothelial cell function. J Lipid Res 53:1304-15|