Molecular Genetics of Coagulation Disorders

描述（由申请人提供）： 凝血和血栓形成的调节异常在许多心、肺和血液疾病的发病机制中起主要作用。 本计划项目将整合一些独立研究者的研究成果，以探索凝血和血栓形成的选定疾病的分子基础以及止血平衡在血管疾病发病机制中的作用。 PPG建立在密歇根大学在人类分子遗传学和血液凝固的细胞和分子生物学方面的现有优势之上。 本提案中的各个项目强调使用新技术来提供更好的生物学见解，并开发出血、血栓形成和相关心血管疾病的新治疗方法。 本PPG中包含的四个单独项目将：1）采用全基因组ENU诱变扫描，以努力鉴定小鼠中因子V Leiden的大量修饰基因，作为导致患有因子V Leiden和其他血栓前疾病的人的血栓形成易感性的候选基因; 2）探索ER加工在凝血FV和FVIII生物合成中的作用，以确定因子V和因子VIII联合缺乏的分子基础，并检查FVIII水平改变作为血栓形成危险因素的作用; 3）和4）研究纤溶系统组分PAI 1和玻连蛋白对动脉粥样硬化发病机制的贡献（3）和对导致新生内膜增生的血管损伤的病理反应（4），以及该系统作为治疗干预靶点的潜力。 PPG将支持4个核心的开发：A）小鼠凝血实验室; B）遗传学核心; C）管理核心和D）形态学核心。 PPG旨在增加项目参与者之间的互动和合作，以及密歇根大学已经从事凝血，血栓形成和血管疾病研究的大量其他实验室之间的互动和合作。 我们预计，通过所有参与者的共同努力，整个计划将大大超过各个部分的总和。

DESCRIPTION (provided by applicant): Abnormalities in the regulation of coagulation and thrombosis play a major role in the pathogenesis of many heart, lung, and blood diseases. This Program Project will integrate the research efforts of a number of independent investigators to explore the molecular basis for selected disorders of coagulation and thrombosis and the role of hemostatic balance in vascular disease pathogenesis. The PPG builds on the existing strength at the University of Michigan in human molecular genetics and cell and molecular biology of blood coagulation. The individual projects in this proposal emphasize the use of new technologies to provide improved biologic insight and develop new treatments for hemorrhage, thrombosis and related cardiovascular disorders. The four individual projects contained in this PPG will: 1) employ a whole genome ENU mutagenesis scan in an effort to identify a large panel of modifier genes for factor V Leiden in the mouse as candidate genes contributing to thrombosis susceptibility in humans with factor V Leiden and other prothrombotic disorders; 2) explore the role of ER processing in coagulation FV and FVIII biosynthesis to identify the molecular basis for combined deficiency of factor V and factor VIII, and examine the role of altered FVIII level as a risk factor for thrombosis; 3) and 4) study the contribution of the fibrinolytic system components PAI1 and vitronectin to the pathogenesis of atherosclerosis (3) and the pathologic response to vascular injury leading to neointimal hyperplasia (4), and the potential of this system as a target for therapeutic intervention. The PPG will support the development of 4 cores: A) the Mouse Coagulation Laboratory; B) the Genetics Core; C) the Administrative Core, and D) the Morphology Core. The PPG will aim to increase interaction and collaboration between individual project participants, as well as among the large number of other laboratories at the University of Michigan already engaged in research on coagulation, thrombosis and vascular disease. We anticipate that the overall program resulting from the combined efforts of all participants will significantly exceed the sum of the individual parts.