Molecular Genetics of Coagulation Disorders

本项目将探讨选定的凝血和血栓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。本提案中的个别项目强调使用新技术来提供改进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。该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突变分析，以鉴定V Leiden因子的遗传修饰因子，同时利用天然小鼠品系变异来鉴定其他血栓形成修饰因子，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。目前的建议侧重于内质网管中错误折叠FVIII导致氧化应激的分子机制；(3)探讨细菌链激酶（SK）及其与纤溶酶原的相互作用在A群链球菌感染发病机制中的作用；高通量化学筛选将用于开发特异性的SK抑制剂，作为治疗这一重要人类感染的潜在新型抗生素。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)行政核心和(D)形态学核心。PPG的目标是增加单个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，所有参与者共同努力的整体计划将大大超过个别部分的总和。与公共卫生的相关性：血液凝固控制异常是许多疾病的关键因素，包括心脏病发作和中风（美国的主要死亡原因），以及一些重要的传染病。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.