Molecular Genetics of Coagulation Disorders

描述(由申请人提供)： 凝血和血栓形成调节的异常在许多心、肺和血液疾病的发病机制中起主要作用。该计划项目将整合多个独立研究人员的研究努力，探索选定的凝血和血栓形成障碍的分子基础，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以及凝血细胞和分子生物学方面的现有实力的基础上。该提案中的个别项目强调使用新技术来提供更好的生物洞察力，并开发治疗出血、血栓形成和相关心血管疾病的新疗法。这份PPG中包含的四个单独项目将：1)采用全基因组ENU突变扫描，努力在小鼠中确定一大组FV Leiden修饰基因作为候选基因，导致患有FV Leiden和其他血栓前疾病的人的血栓形成易感性；2)探索ER加工在凝血FV和FVIII生物合成中的作用，以确定FV和FVIII联合缺陷的分子基础，并检查FVIII水平改变作为血栓形成的危险因素的作用；3)和4)研究纤溶系统组分PAI1和Vitronectin在动脉粥样硬化发病机制中的作用(3)和血管损伤导致新生内膜增生的病理反应(4)，以及该系统作为治疗干预靶点的可能性。PPG将支持4个核心的开发：A)老鼠凝血实验室；B)遗传学核心；C)管理核心；以及D)形态核心。PPG将致力于加强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，由所有参与者共同努力产生的整体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.