Pathophysiologies Involving Hemostasis-related Genes

涉及止血相关基因的病理生理学

• 批准号: 7052892
• 负责人: FRANCIS J CASTELLINO
• 金额: $ 176.05万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052892
• 关键词: blood coagulation; gene mutation; genetically modified animals; hemostasis; laboratory mouse; molecular pathology; pathologic process

It is becoming increasingly clear that genes traditionally associated with hemostasis function in many other diverse pathophysiologic processes. Examples are the involvement of gene products related to fibrinolysis, e.g., plasminogen, plasminogen activators, and plasminogen activator inhibitors, with their roles in cancer, wound healing, and angiogenesis. These same genes, as well as products of genes of relevance to coagulation, e.g., Tissue Factor, and anticoagulation, e.g., Protein C, also function in embryogenesis, cancer, and acute and chronic inflammatory-based processes, among others. Thus, hemostasis-related genes serve as links between different pathways in health and disease. This Program Project Grant (PPG) builds on existing strengths and integrates the research efforts of experienced investigators who have made major contributions to our understanding of the protein chemistry, molecular and cell biology, gene targeting, and pathophysioiogies of proteins and genes associated with hemostasis. The focus of this PPG is the definition of the in vivo roles of hemostasis-related genes in: the relationships between disseminated intravascular coagulation, systemic inflammation, and organ damage during the progression of sepsis (Project by Castellino); tumorigenesis, metastasis, and angiogenesis (Project by Ploplis); and embryonic and perinatal survival of offspring, as well as in vivo thrombus formation (Project by Rosen). Three core units are proposed as necessary to centrally support this group of projects: (1) an Administrative Core, (2) an Anatomic Pathology Core, and (3) a Mouse Breeding and Husbandry Core. The Project and Core Leaders have a long history of productive interactions with each other and are all based in an infrastructure-rich center devoted to in vivo and in vitro studies of coagulation, anticoagulation, and fibrinolysis. The projects proposed will utilize the same administrative, histopathology, and mouse cores. The PPG will allow increased interactions and collaborations to occur between the laboratories of the Project Leaders in studying the functional roles of hemostasis-related genes, and the overall program that results from these combined efforts will exceed the sum of the individual parts. The research efforts and productivity of students and postdoctorals will benefit greatly from the interactions of the individual laboratories and cores that will result from the PPG, and will serve as a resource for a continual flow of independent investigations in these research areas.

越来越清楚的是，传统上与止血功能相关的基因在许多其他不同的病理生理过程中发挥作用。例子是与纤维蛋白溶解相关的基因产物的参与，例如，纤溶酶原、纤溶酶原激活剂和纤溶酶原激活剂抑制剂，以及它们在癌症、伤口愈合和血管生成中的作用。这些相同的基因，以及与凝血相关的基因的产物，例如，组织因子和抗凝，例如，蛋白C也在胚胎发生、癌症以及基于急性和慢性炎症的过程中起作用。因此，止血相关基因作为健康和疾病的不同途径之间的联系。该计划项目资助（PPG）建立在现有优势的基础上，并整合了经验丰富的研究人员的研究成果，这些研究人员为我们理解蛋白质化学，分子和细胞生物学，基因靶向以及与止血相关的蛋白质和基因的病理生理学做出了重大贡献。本PPG的重点是定义止血相关基因在以下方面的体内作用：脓毒症进展期间弥散性血管内凝血、全身性炎症和器官损伤之间的关系（Castellino项目）;肿瘤发生、转移和血管生成（Ploplis项目）;后代的胚胎和围产期存活率以及体内血栓形成（罗森项目）。根据需要提议设立三个核心单位， 中心支持这组项目：（1）管理核心，（2）解剖病理学核心，（3）小鼠育种和畜牧核心。该项目和核心领导人有着悠久的历史，彼此之间有着富有成效的互动，并且都位于一个基础设施丰富的中心，致力于凝血，抗凝和纤溶的体内和体外研究。拟议的项目将使用相同的管理、组织病理学和小鼠核心。PPG将允许项目负责人的实验室之间在研究止血相关基因的功能作用方面进行更多的互动和合作，并且这些联合努力产生的整体计划将超过单个部分的总和。学生和博士后的研究工作和生产力将大大受益于PPG产生的各个实验室和核心的相互作用， 作为这些研究领域中独立调查的持续流动的资源。