Hemostatic Factors and Tumor Biology

止血因素与肿瘤生物学

• 批准号: 6672261
• 负责人: JOSEPH S. PALUMBO
• 金额: $ 13.04万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6672261
• 关键词: cell migration; cytotoxicity; disease /disorder model; fibrin; fibrinogen; fibrinogen receptors; gene targeting; genetically modified animals; hemostasis; immunity; laboratory mouse; metastasis; natural killer cells; platelet activation; platelets; protein protein interaction; radiotracer; receptor binding; receptor expression

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.

描述（由申请人提供）： 先前的研究表明，纤维蛋白原是转移潜能的重要决定因素，可能是通过自然杀伤细胞影响肿瘤细胞清除率的。然而，血小板/纤维蛋白原轴影响恶性肿的精确机制仍然很少理解。该提案中详细介绍的实验将使用靶向基因的技术和体内鼠肿瘤模型来定义血小板激活，纤维蛋白（OGEN）和血小板/纤维蛋白相互作用在转移和天然杀伤细胞介导的肿瘤测量中的作用。此外，将探索Mac-1介导的纤维蛋白（OGEN）/NK细胞相互作用在NK细胞介导的肿瘤清除率中的机械意义。提出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 - 合格蛋白（OGEN）相互作用是确定转移性潜力的血小板/纤维蛋白原轴的关键决定因素；杀伤细胞）和3）Beta2整合蛋白Mac-L的纤维蛋白（OGEN）参与是先天免疫的肿瘤呼叫清除的机械决定因素。该提案将为申请人提供一个极好的机会，以扩大其在分子遗传学，免疫学肿瘤生物学和病理学方面的技能。申请人将获得赞助商Jay Degen，Ph.D.的密切指导，这是分子止血和基因靶向的公认领导者。辛辛那提儿童医院研究基金会将是完成该建议的绝佳场所，为申请人提供最新的资源和专业知识。咨询委员会由分子免疫学，肿瘤生物学，造血和信号传导的专家组成，申请人将受益于理想的培训环境。计划中的计划将提供生产力，知识和技能的记录，以建立作为独立医师/科学家的成功职业。