Nitric Oxide Regulation of Platelet Granule Exocytosis

描述（由申请人提供）： 我正在申请指导临床科学家职业奖（K08），以获得指导基础研究培训。 我希望研究一氧化氮对血小板颗粒胞吐作用的调节，因为它与血栓形成有关。 通过这个奖项，我希望成为一名能够通过以下方式应用我的知识和培训的研究员：1）以实验室为基础的指导组件，以获得（a）胞吐研究和（B）血栓形成研究方面的知识; 2）以比较医学为基础的组件; 3）咨询委员会;以及4）以约翰霍普金斯医学研究所为基础的组件。 研究指导将由心脏病专家、一氧化氮（NO）和NO合酶研究专家Charles Lowenstein博士提供。 特别是，他的实验室探索了NO调节血管炎症的机制。 我的具体研究计划旨在确定NO在调节血小板颗粒胞吐中的作用。 特别是，我感兴趣的是NO修饰的分子N-乙基马来酰亚胺敏感因子（NSF），参与调节胞吐在许多细胞类型的分子。 我的具体目标是证明：1）NO调节血小板颗粒胞吐作用; 2）NO调节体外和体内NSF活性; 3）NSF的肽抑制剂在体外抑制NSF，从而抑制体内血栓形成。 血管炎症是许多心血管疾病的重要组成部分。 血小板衍生的血栓前介质和炎症介质，例如在血小板颗粒中发现的那些，是促进血小板和白细胞（特别是中性粒细胞）定位于血管损伤部位的关键，并可能加重损伤。 因此，减少颗粒胞吐的策略可能在血栓前疾病的急性治疗中证明是有价值的。 (End摘要）

DESCRIPTION (provided by applicant): 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)