Endothelial Cell Mechanical Dysfunction in Early Stage Atherosclerosis

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 DESCRIPTION (provided by applicant): The PI is an assistant professor and the first dual hire between the Department of Mechanical and Aerospace Engineering and College of Medicine at the University of Central Florida. His background is in mechanical engineering and his research experiences have primarily focused on the development of technologies to mechanically stimulate mammalian cells and investigation of associated morphological responses. A total of thirteen publications have been produced thus far, including five first-author publications, two book chapters, and one equal contribution. The PI is highly motivated become an independent investigator in the cardiovascular field, but the PI's past research to date has only been peripherally related to the field. Furthermore, the PI believes the best treatment for many cardiovascular diseases is prevention at its earliest stages. Early stage atherosclerosis, for example, involves the entry and accumulation of low density lipoprotein (LDL) within the endothelium and leukocyte transmigration across the endothelium eventually yielding foam cells, the precursors of atherosclerotic plaques 1-9. Present during each of the previously mentioned processes within the endothelial monolayer are innate cell-cell adhesion forces10-15, whose roles and underlying biomolecular components have yet to be discovered. Therefore, the proposed award will investigate the hypothesis that decreased cell-cell junction activity decreases cell-cell adhesion forces, prompting increased LDL penetration and increased leukocyte transmigration across the endothelium under disturbed fluid flow. To test the above hypothesis a training plan is proposed that will allow the PI to develop expertise essential to the completion of this project in the following fields; molecular biology, atherosclerosis, and immunology. To ensure that the PI gains these skill sets the PI will be mentored by Dr. Sampath Parthasarathy. Dr. Parthasarathy is an internationally recognized authority on atherosclerosis. He has published over 150 papers on the topic (out of over 250) and has written a text book on "Modified Lipoproteins in the Pathogenesis of Atherosclerosis". His mentoring and guidance will therefore be invaluable to the success of the PI. Furthermore, the PI's training will take place in UCF's College of Medicine, which is located on Orlando's Medical City campus. This health and life sciences research park also includes the Sanford-Burnham Medical Research Institute, Nemour's Children Hospital, and Veterans Affairs Orlando Medical Center, providing an ideal biomedical research environment for the PI. Successful completion of this training award will put the PI on a career path to achieve the following goals; 1) to become an established investigator in the cardiovascular field and 2) obtain preliminary data to apply for future RO1 funding. In addition, the very long term career goal of the PI is to establish a multidisciplinary research tea that will consist of other independent investigators who are engineers, clinicians, and scientists to apply for PO1 funding and establish a research program in cardiovascular pathology aimed at developing novel bench-to-bedside cardiovascular therapies that would consist of treating cardiovascular disease at the cellular level.