Hemostatic Factors and Tumor Biology

描述(由申请人提供)： 以前的研究表明，纤维蛋白原是转移潜能的重要决定因素，可能是通过影响自然杀伤细胞对肿瘤细胞的清除而实现的。然而，血小板/纤维蛋白原轴影响恶性肿瘤的确切机制(S)仍然知之甚少。提案中详细介绍的实验将使用基因打靶技术和体内小鼠肿瘤模型来确定血小板激活、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，还将探讨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)血小板激活、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)-血小板微血栓是与肿瘤免疫相关的细胞(即自然杀伤细胞)运输和/或激活的重要因素，以及3)β2-整合素与纤维蛋白(原)的结合，Mac-L是天然免疫清除肿瘤信号的机制决定因素。这项提议将为申请者提供一个极好的机会来扩大他在分子遗传学、免疫学、肿瘤生物学和病理学方面的技能。申请者将得到赞助商杰伊·德根博士的密切指导，他是分子止血和基因靶向领域的公认领导者。辛辛那提儿童医院研究基金会将是完成这项提案的绝佳环境，为申请者提供获得最先进的资源和专业知识的途径。与由分子免疫学、肿瘤生物学、造血和信号转导专家组成的咨询委员会一起，申请者将受益于理想的培训环境。计划中的计划将提供作为一名独立医生/科学家建立成功职业生涯所需的生产力、知识和技能的记录。

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.