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There is now a CONTENT FREEZE for Mercury while we switch to a new platform. It began on Friday, March 10 at 6pm and will end on Wednesday, March 15 at noon. No new content can be created during this time, but all material in the system as of the beginning of the freeze will be migrated to the new platform, including users and groups. Functionally the new site is identical to the old one. webteam@gatech.edu
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Thesis Advisor:
Dr. Manu Platt (Georgia Institute of Technology and Emory University)
Committee:
Dr. Robert Taylor ( Emory University and Georgia Institute of Technology)
Dr. Suzanne Eskin (Georgia Institute of Technology)
Dr. Rudy Gleason (Georgia Institute of Technology and Emory University)
Dr. Roy Sutliff (Emory University)
Major advances in highly active antiretroviral therapies (HAART) have extended the lives of people living with HIV, but there still remains an increased risk of death by cardiovascular diseases (CVD). HIV proteins have been shown to contribute to cardiovascular dysfunction with effects on the different cell types that comprise the arterial wall. In particular, HIV-1 transactivating factor, Tat, is a cationic polypeptide that binds to endothelial cells and activates monocytes, inducing a range of responses that have been shown to contribute to vascular dysfunction. It is well established that hemodynamics also play an important role in endothelial cell mediated atherosclerotic development where upon exposure to low or oscillatory shear stress, such as that found at branches and bifurcations, endothelial cells contribute to proteolytic vascular remodeling, by upregulating cathepsins, potent elastases and collagenases. Mechanisms to understand the influence of HIV proteins on shear mediated vascular remodeling have not been fully elucidated. Our central hypothesis is that HIV-1 Tat contributes to arterial remodeling at regions of low and oscillatory shear stress by increasing cathepsin expression even beyond that of the endothelial cell response to disturbed flow, serving to modify extracellular matrix content and organization, ultimately leading to altered arterial biomechanics and increased arterial stiffness which promotes cardiovascular disease. The aims of this project are to examine the effects of HIV-1 Tat protein and atherogenic shear conditions on the proteolytic activity of endothelial cells, and specifically determine regulatory mechanisms downstream of Tat activation of endothelial cells and monocyte binding using in vitro culture systems and the HIV-transgenic mouse model.
