? ? I am applying for a Mentored Clinical Scientist Career Award (K08) in order to gain mentored basic research training. I wish to investigate nitric oxide regulation of platelet granule exocytosis as it relates to thrombosis. Through this award I seek to become an investigator capable of applying my knowledge and training through 1) a mentored laboratory-based component to acquire knowledge in (a) exocytosis research and (b) thrombosis research; 2) a comparative medicine-based component; 3) an advisory committee; and 4) a general Johns Hopkins Medical Institute-based component. Research mentorship will be provided by Dr. Charles Lowenstein, a cardiologist and an expert in nitric oxide (NO) and NO synthase research. In particular, his laboratory explores mechanisms by which NO regulates vascular inflammation. ? ? My specific research proposal is aimed at defining the role of NO in regulating platelet granule exocytosis. In particular, I am interested in NO modification of the molecule N-ethylmaleimide sensitive factor (NSF), a molecule involved in regulating exocytosis in many cell types.
My specific aims are intended to demonstrate that: 1) NO regulates platelet granule exocytosis: 2) NO regulates NSF activity in vitro and in vivo; and 3) peptide inhibitors of NSF inhibit NSF in vitro and therefore inhibit thrombosis in vivo. ? ? Vascular inflammation is an important component of many cardiovascular diseases. Platelet-derived prothrombotic and inflammatory mediators, such as those found in platelet granules, are key in promoting localization of platelets and leukocytes (neutrophils, in particular) to the sites of vascular injury and may exacerbate the injury. Therefore, strategies to minimize granule exocytosis may prove valuable in the acute treatment of pro-thrombotic diseases. (End of Abstract) ? ?
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