Molecular Genetics of Coagulation Disorders

本计画将探讨凝血与血栓形成之分子基础，以及止血平衡在血管疾病发病机制中之角色。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中包含的三个单独项目将：（1）继续在小鼠中进行全基因组ENU诱变分析，以鉴定因子V Leiden的遗传修饰物，同时还利用天然鼠品系变异来鉴定其他血栓形成修饰物，以及血栓性血小板减少性紫癜（TTP）的修饰基因;（2）继续探索限制因子VIII表达的关键因素。目前的建议集中在负责氧化应激的分子机制，导致错误折叠的FVIII在ER腔;和（3）探讨细菌链激酶（SK）的作用及其与纤溶酶原在A组链球菌感染的发病机制的相互作用;高通量化学筛选将用于开发特定的SK抑制剂作为一个潜在的新型抗生素，这种重要的人类感染。PPG将继续支持4个核心：（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。与公共卫生的相关性：血液凝固的控制是许多疾病的关键因素，包括心脏病发作和中风（美国死亡的主要原因），以及几种重要的传染病。该项目将确定该系统中的关键基因，这些基因将提供有价值的新诊断工具，并提出新的治疗方法。

This Program Project will explore the molecular basis for selected disorders of coagulation and thrombosis and the role of hemostatic balance in vascular disease pathogenesis. 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 three individual projects contained in this PPG will: (1) continue a whole genome ENU mutagenesis analysis in the mouse to identify genetic modifiers of factor V Leiden, while also taking advantage of natural murine strain variation to identify additional thrombosis modifiers, as well as modifier genes for thrombotic thrombocytopenic purpura (TTP); (2) continue to explore the critical factors that limit factor VIII expression. The current proposal focuses on the molecular mechanisms responsible for the oxidative stress that results from misfolded FVIII in the ER lumen; and (3) explore the role of bacterial streptokinase (SK) and its interaction with plasminogen in the pathogenesis of Group A streptococcal infection; high throughput chemical screening will be used to develop specific SK inhibitors as a potential new class of antibiotics for this important human infection. The PPG will continue to support 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. Relevance to public health: Abnormalities in the control of blood clotting are a critical factor in a number of diseases, including heart attack and stroke (the leadings causes of death in the US), as well as several important infectious diseases. This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment.