The Molecular Genetics of Hemostasis

止血的分子遗传学

• 批准号: 10377324
• 负责人: David Ginsburg
• 金额: $ 58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-10 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377324
• 关键词: Address; Amino Acid Substitution; Area; Back; Biological Process; Blood Coagulation Disorders; Blood coagulation; Cell physiology; Cholesterol; Chromosome 2; Chromosome 5; Clinical; Congenital dyserythropoietic anemia; DNA Sequence; Data; Data Set; Development; Diagnosis; Disease; Disease susceptibility; Equipment and supply inventories; Factor V Deficiency; Factor VIII; Foundations; Future; Gene-Modified; Genes; Genetic; Genetic Diseases; Genomics; Golgi Apparatus; Heart Diseases; Hematological Disease; Hemorrhage; Hemostatic function; Human; Human Chromosomes; Human Genetics; Inherited; Laboratory mice; Lead; Maps; Modeling; Molecular; Molecular Genetics; Mus; Mutagenesis; Mutation; Other Genetics; Pathogenesis; Pathway interactions; Patients; Plasma; Predisposition; Regulation; Regulator Genes; Research; Risk; Risk Factors; Role; Selection for Treatments; Sequence Analysis; Severities; Suppressor Genes; System; Technology; Thrombocytopenia; Thrombosis; Thrombotic Thrombocytopenic Purpura; Venous; Venous Thrombosis; Work; bench to bedside; bench-to-bedside translation; cohort; genome editing; human disease; human subject; improved; individual patient; insight; novel; novel strategies; novel therapeutics; precision medicine; programs; protein transport; thrombotic; tool; variant of unknown significance; von Willebrand Disease; von Willebrand Factor; whole genome

PROJECT SUMMARY This proposal will continue the longstanding focus of this research program in 3 related areas: 1) the molecular pathogenesis of disorders in von Willebrand factor (VWF) function, 2) the genetic factors that modify the manifestations of other inherited bleeding and blood clotting diseases, and 3) regulation of protein transport from the ER to the Golgi apparatus and its role in the pathogenesis of blood diseases. VWF is a key component of the blood coagulation system whose deficiency resulting in the most common inherited bleeding disorder in humans, von Willebrand disease (VWD). Elevated levels of VWF are a major risk factor for thrombosis, with loss of VWF processing by ADAMTS13 resulting in thrombotic thrombocytopenic purpura (TTP). This project will exploit recent transformative advances in genomic technology to uncover novel pathways contributing to the control of VWF and ADAMTS13 function and lay the foundation for a “precision medicine” approach to these disorders. A novel VWF regulatory gene previously mapped to human chromosome 2 will be identified through genomic sequence analysis in an additional large cohort of human subjects and its function explored through modeling by “genome editing” in laboratory mice. Similar tools will be used to characterize a novel modifier gene for TTP susceptibility mapped to mouse chromosome 5. We will also assemble a comprehensive dataset for the functional impact of all possible single amino acid substitutions within the VWF A1 and A2 domains to provide a complete inventory of potential human mutations causing type 2A, 2M and 2B VWD. These data will address the increasingly important clinical problem of “variant of uncertain significance”, a key challenge for the entire field of human genetics, and should lay the foundation for eventual diagnosis and subclassification of VWD on the basis of DNA sequence alone, enabling true “precision medicine”, and serving as a useful paradigm for other genetic diseases. This program will also focus on identifying novel genes that contribute to venous thromboembolic (VTE) disease susceptibility, both by direct genomic sequence analysis in human VTE patients, as well as a broad whole genome mutagenesis screen for thrombosis suppressor genes in laboratory mice. Finally, in a “bedside” to “bench” translation, the lab has broadened its studies of the rare inherited bleeding disorder, combined deficiency of factors V and VIII, to explore the basic function of cellular transport pathways leading to unexpected insights into the molecular pathogenesis of congenital dyserythropoietic anemia II and the regulation of plasma cholesterol levels. These findings are now circling back from the “bench” to the “bedside”, with the potential to provide improved diagnosis and therapy for related diseases. Taken together, this research program will apply cutting-edge genetic and genomic technologies to identify critical genes modifying the risk and severity for a number of blood and heart diseases, as well as yielding information about fundamental biologic processes that could lay the ground work for future novel approaches to the diagnosis and treatment of these disorders.

项目概要 该提案将继续该研究计划在 3 个相关领域的长期重点：1） 血管性血友病因子 (VWF) 功能障碍的分子发病机制，2) 改变的遗传因素 其他遗传性出血和凝血疾病的表现，3) 蛋白质转运的调节 从内质网到高尔基体及其在血液疾病发病机制中的作用。 VWF是关键 凝血系统的组成部分，其缺陷导致最常见的遗传性出血 人类疾病，冯维勒布兰德病（VWD）。 VWF 水平升高是一个主要危险因素 血栓形成，ADAMTS13 处理 VWF 的功能丧失导致血栓性血小板减少性紫癜 （TTP）。该项目将利用基因组技术的最新变革性进展来发现新的 有助于控制 VWF 和 ADAMTS13 功能的途径，并为“精确 医学”的方法来治疗这些疾病。一种新的 VWF 调节基因，之前映射到人类 2号染色体将通过基因组序列分析在另外一大群人类中进行鉴定 通过对实验室小鼠进行“基因组编辑”建模来探索受试者及其功能。类似的工具将 用于表征映射到小鼠 5 号染色体的 TTP 易感性的新型修饰基因。我们将 还构建了一个全面的数据集，用于了解所有可能的单一氨基酸取代的功能影响 在 VWF A1 和 A2 域内，提供潜在人类突变引起类型的完整清单 2A、2M 和 2B VWD。这些数据将解决日益重要的“变体”临床问题 不确定的意义”，这是整个人类遗传学领域的一个关键挑战，应该为 仅基于 DNA 序列即可对 VWD 进行最终诊断和细分，从而实现真正的“精准” 医学”，并作为其他遗传疾病的有用范例。该计划还将重点关注 通过直接识别导致静脉血栓栓塞 (VTE) 疾病易感性的新基因 人类 VTE 患者的基因组序列分析，以及广泛的全基因组突变筛选 实验室小鼠的血栓形成抑制基因。最后，在“床边”到“工作台”的翻译中，实验室已经 扩大了对罕见遗传性出血性疾病（因子 V 和 VIII 联合缺乏）的研究， 探索细胞运输途径的基本功能，从而获得对分子的意想不到的见解 先天性红细胞生成障碍性贫血II的发病机制和血浆胆固醇水平的调节。这些 研究结果现在正从“工作台”回到“临床”，有可能提供改进的结果 相关疾病的诊断和治疗。总而言之，该研究计划将应用尖端技术 遗传和基因组技术可识别改变许多疾病风险和严重程度的关键基因 血液和心脏病，以及产生有关基本生物过程的信息，这些信息可以奠定 为未来诊断和治疗这些疾病的新方法奠定基础。