This revised proposal describes a 5-year training program for career development in academic cardiovascular (CV) medicine. The principal investigator has completed clinical and research training in CV medicine at Brigham and Women's Hospital and will embark on a research program designed to provide additional scientific training required for an independent biomedical research career. This program will provide in-depth knowledge and experience in biochemistry, cellular biology, and in vivo animal studies applied to thrombosis and atherosclerosis. Dr. Peter Libby will mentor the principal investigator's scientific development and Dr. Simon will serve as co-mentor. Dr. Libby is a recognized leader in the field of vascular inflammation and atherosclerosis and has a successful track record in basic and translational vascular biology research. The training experience will be enhanced through collaborative intravital microscopy studies with Dr. Bruce Furie, a leader in thrombosis research. An advisory committee of expert medical scientists (Drs. Daniel Simon, Bruce Furie, Tanya Mayadas-Norton) will provide scientific and career advice. The central hypotheses of this proposal are that MRP-14 modulates platelet and monocyte function and that platelet- and leukocyte-derived MRP-14 affect vascular inflammation and atherogenesis. Preliminary data have identified MRP-14 as a platelet transcript that is elevated in patients on presentation with acute myocardial infarction (Ml) and, in two validation case-control studies, MRP-8/14 predicts risk of Ml. The overall objective of this proposal is to determine the role of MRP-14 in atherothrombotic disease.
The specific aims are: 1) to investigate the role of MRP-14 in regulating platelet and monocyte function in vitro;2) to determine whether MRP-14 modulates arterial thrombosis in vivo;and 3) to examine the role of MRP-14 in vascular inflammation and atherogenesis in vivo. These studies will exploit the use of wild-type and MRP-14-deficient mice. Identification of molecules involved in atherothrombosis will provide potential targets for therapies to prevent heart attack and stroke. The Harvard Medical School/Brigham and Women's Hospital Center of Excellence in Vascular Biology is an exceptional environment that will provide innumerable resources to accelerate the applicant's training for an independent career in academic research.
|Brown, Jonathan D; Lin, Charles Y; Duan, Qiong et al. (2014) NF-?B directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 56:219-31|
|Wang, Yunmei; Fang, Chao; Gao, Huiyun et al. (2014) Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis. J Clin Invest 124:2160-71|
|Azcutia, Veronica; Routledge, Matthew; Williams, Marcie R et al. (2013) CD47 plays a critical role in T-cell recruitment by regulation of LFA-1 and VLA-4 integrin adhesive functions. Mol Biol Cell 24:3358-68|
|New, Sophie E P; Goettsch, Claudia; Aikawa, Masanori et al. (2013) Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res 113:72-7|
|Maiseyeu, Andrei; Badgeley, Marcus A; Kampfrath, Thomas et al. (2012) In vivo targeting of inflammation-associated myeloid-related protein 8/14 via gadolinium immunonanoparticles. Arterioscler Thromb Vasc Biol 32:962-70|
|Alcaide, Pilar; Maganto-Garcia, Elena; Newton, Gail et al. (2012) Difference in Th1 and Th17 lymphocyte adhesion to endothelium. J Immunol 188:1421-30|
|Shimizu, Koichi; Libby, Peter; Rocha, Viviane Z et al. (2011) Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection. Circulation 124:2920-32|
|Maganto-García, Elena; Bu, De-Xiu; Tarrio, Margarite L et al. (2011) Foxp3+-inducible regulatory T cells suppress endothelial activation and leukocyte recruitment. J Immunol 187:3521-9|
|Jin, Richard C; Mahoney, Christopher E; Coleman Anderson, Laura et al. (2011) Glutathione peroxidase-3 deficiency promotes platelet-dependent thrombosis in vivo. Circulation 123:1963-73|
|Inoue, Teruo; Croce, Kevin; Morooka, Toshifumi et al. (2011) Vascular inflammation and repair: implications for re-endothelialization, restenosis, and stent thrombosis. JACC Cardiovasc Interv 4:1057-66|
Showing the most recent 10 out of 18 publications