Hemostatic Factors and Tumor Biology

描述（由申请人提供）： 先前的研究表明，纤维蛋白原是转移潜力的重要决定因素，可能通过影响自然杀伤细胞对肿瘤细胞的清除。然而，血小板/纤维蛋白原轴影响恶性肿瘤的确切机制仍然知之甚少。该提案中详述的实验将使用基因靶向技术和体内小鼠肿瘤模型来确定血小板活化、纤维蛋白（原）和血小板/纤维蛋白相互作用在转移和自然杀伤细胞介导的肿瘤监测中的作用。此外，将探索Mac-1介导的纤维蛋白（原）/NK细胞相互作用在NK细胞介导的肿瘤清除中的机制意义。拟议的实验将检验以下假设：1）血小板活化、纤维蛋白聚合物形成和血小板-纤维蛋白（原）相互作用是决定转移潜能的血小板/纤维蛋白原轴的关键决定因素，2）肿瘤细胞相关的纤维蛋白（原）-血小板微血栓是与先天性肿瘤免疫相关的细胞运输和/或活化的重要因素（即自然杀伤细胞），和3）β 2-整联蛋白Mac-I的纤维蛋白（原）接合是先天免疫清除肿瘤细胞的机制决定因素。该提案将为申请人提供一个极好的机会，以扩大他的技能，分子遗传学，免疫学肿瘤生物学和病理学。申请人将受益于赞助商Jay Degen博士的密切指导，分子止血和基因靶向领域公认的领导者。该辛辛那提儿童医院研究基金会将是一个很好的设置完成这一建议，为申请人提供访问国家的最先进的资源和专业知识。与由分子免疫学，肿瘤生物学，造血和信号专家组成的咨询委员会一起，申请人将受益于理想的培训环境。该计划将提供必要的生产力，知识和技能的记录，以建立一个成功的职业生涯作为一个独立的医生/科学家。

DESCRIPTION (provided by applicant): Previous studies have demonstrated that fibrinogen is an important determinant of metastatic potential, possibly by influencing tumor cell clearance by natural killer cells. However, the precise mechanism(s) by which the platelet/fibrinogen axis influences malignancy remain poorly understood. The experiments detailed in the proposal will use gene-targeting technology and in vivo murine tumor models to define the role of platelet activation, fibrin(ogen) and platelet/fibrin interactions in metastasis and natural killer cell mediated tumor surveillance. Additionally, the mechanistic significance of Mac-1 mediated fibrin(ogen)/NK cell interactions in NK cell mediated tumor clearance will be explored. The proposed experiments will test the following hypotheses: 1) platelet activation, fibrin polymer formation and platelet-fibrin(ogen) interactions are key determinants of the platelet/fibrinogen axis that determine metastatic potential, 2) tumor cell associated fibrin(ogen)-platelet microthrombi are an important factor in the trafficking and/or activation of cells related to innate tumor immunity (i.e. natural killer cells), and 3) fibrin(ogen) engagement of the beta2- integrin, Mac-l, is a mechanistic determinant of tumor call clearance by innate immunity. The proposal will provide an excellent opportunity for the applicant to expand his skills in molecular genetics, immunology tumor biology and pathology. The applicant will have the benefit of close mentorship by the sponsor, Jay Degen, Ph.D., a recognized leader in the field of molecular hemostasis and gene-targeting. The Cincinnati Children's Hospital Research Foundation will be an excellent setting for completing this proposal, providing the applicant with access to state-of-the-art resources and expertise. Together with an advisory committee consisting of experts in molecular immunology, tumor biology, hematopoiesis and signaling, the applicant will have the benefit of an ideal training environment. The planned program will provide the record of productivity, knowledge and skills necessary to establish a successful career as an independent physician/scientist.