MRP-14, Platelets and Atherothrombosis

描述（由申请人提供）： 本修订提案描述了一个为期5年的学术心血管（CV）医学职业发展培训计划。主要研究者已在布里格姆妇女医院完成了CV医学的临床和研究培训，并将开始一项研究计划，旨在提供独立生物医学研究职业所需的额外科学培训。该计划将提供深入的知识和经验，在生物化学，细胞生物学，并在体内动物研究应用于血栓形成和动脉粥样硬化。Peter Libby博士将指导主要研究者的科学发展，Simon博士将担任共同导师。利比博士是血管炎症和动脉粥样硬化领域公认的领导者，在基础和转化血管生物学研究方面有着成功的记录。培训经验将通过与血栓形成研究的领导者布鲁斯福瑞博士合作的活体显微镜研究得到加强。一个由医学专家（丹尼尔西蒙博士、布鲁斯福瑞博士、坦尼娅·马雅达斯·诺顿博士）组成的咨询委员会将提供科学和职业建议。该提议的中心假设是MRP-14调节血小板和单核细胞功能，并且血小板和白细胞衍生的MRP-14影响血管炎症和动脉粥样硬化形成。初步数据已经将MRP-14鉴定为在呈现急性心肌梗塞（MI）的患者中升高的血小板转录物，并且在两个验证病例对照研究中，MRP-8/14预测MI的风险。本研究的总体目标是确定MRP-14在动脉粥样硬化性血栓形成疾病中的作用。具体目标是：1）研究MRP-14在体外调节血小板和单核细胞功能中的作用; 2）确定MRP-14是否在体内调节动脉血栓形成;和3）检查MRP-14在体内血管炎症和动脉粥样硬化形成中的作用。这些研究将利用野生型和MRP-14缺陷型小鼠。参与动脉粥样硬化血栓形成的分子的鉴定将为预防心脏病发作和中风的治疗提供潜在的靶点。哈佛医学院/布里格姆妇女医院血管生物学卓越中心是一个特殊的环境，将提供无数的资源，以加速申请人的培训，为学术研究的独立职业生涯。 (End摘要）

DESCRIPTION (provided by applicant): 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. (End of Abstract)