For the past 17 years, investigators at Emory have been studying the sources, regulation and functional implications of reactive oxygen species (ROS) and inflammation in vascular biology and disease. Our PPG application builds on this expertise to test the overall hypothesis that ROS within the vessel wall lead to inflammatory processes that are central mediators of vascular disease. In project 1, Dr. David Harrison proposes that pre-activation of T-cells augments hypertension and will investigate the role of these cells in modulating vascular renal function. He will also study the role of IL-17 in mediating this effect, and test the antihypertensive potential of two therapies to inhibit T cell activation and homing. In project 2, Dr. Hanjoong Jo will investigate an exciting new hypothesis that loss of the bone morphogenic protein type II receptor (BMPRII), such as occurs in response to the inflammatory cytokine TNF-a, unleashes signaling proteins that are normally bound to the receptor and kept inactive, resulting in an uncontrolled activation of inflammatory pathways and the development of atherosclerosis. Dr. Jo will combine cell culture studies aimed at defining the mechanism underlying BMPRII regulation with studies using newly created, endothelial-specific BMPRlT'"""""""" ApoE''mice to test these mechanisms in vivo. In project 3, Dr. W. Robert Taylor will examine the overall role of the receptor for advanced glycation end products (RAGE) in inhibiting collateral vessel formation in normal and diabetic conditions, focusing on the specific contributions of RAGE in monocytes and T cells, which are critical for the formation of collateral blood vessels. Additional studies will examine the ROS-dependent signaling to inflammatory gene expression, migration and cell viability. Project 4 will be directed by Dr. Kathy Grlendling, who proposes to study the differential roles of the NADPH oxidases Noxl and Nox4 in collateral formation and neointimal growth after vascular injury. This project includes studies designed to understand the mechanisms responsible for the opposite regulation of Noxl and Nox4, as well as the role of Nox4 in mediating the protective effects of BMP4. Dr. Grlendling will make use of Noxl and Nox4 knockout mice to investigate the function of these proteins in vivo. Four cores will support these projects. An administrative core, led by Dr. Grlendling, will provide administrative support for the program. A ROS core, led by Dr. Sergey Dikalov, will support state-of-the-art measurements of ROS, and a microscopy and histology core directed by Dr. Lula Hilenski will furnish expertise in confocal microscopy and imaging of inflammatory markers and ROS in cells and tissues. Finally, Dr. Bernard Lass^gue will lead an animal core to centralize rodent genotyping and husbandry. Overall, this research program will provide substantial new information defining the integrated mechanisms by which ROS and inflammation contribute to vascular disease. Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies.
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