The Molecular Genetics of Hemostasis

止血的分子遗传学

基本信息

批准号：
10570867
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
项目类别：
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/10570867
关键词：
ADAMTS Amino Acid Substitution Area Back Biological Process Blood Coagulation Disorders Blood coagulation Cell physiology Cholesterol Chromosome 2 Chromosome 5 Classification 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 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

项目摘要

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.

项目摘要该建议将继续在3个相关领域的研究计划中长期关注：1） Von Willebrand因子（VWF）功能中疾病的分子发病机理，2）修改的遗传因子其他遗传出血和血液凝血疾病的表现，以及3）调节蛋白质转运从ER到高尔基体及其在血液疾病发病机理中的作用。 vwf是关键血液凝结系统的组成部分，其缺乏导致最常见的遗传出血人类的疾病，冯·威勒氏病（VWD）。 VWF的水平升高是血栓形成，ADAMTS13失去VWF处理，导致血小板细胞减少紫红色（TTP）。该项目将利用基因组技术的最新变革性进步来揭示小说有助于控制VWF和ADAMTS13功能的途径，并为“精度”奠定了基础这些疾病的医学方法。染色体2将通过基因组序列分析在其他大型人群中鉴定受试者及其功能通过实验室小鼠中的“基因组编辑”进行建模探索。类似的工具也会用于表征映射到小鼠5号染色体的TTP易感性的新型修饰符基因。我们将还组装一个全面的数据集，以实现所有可能的单个氨基酸取代的功能影响在VWF A1和A2域内，提供了造成类型的潜在人类突变的完整清单 2A，2M和2B VWD。这些数据将解决越来越重要的临床问题“变体不确定的意义”，这是整个人类遗传学领域的关键挑战，应该为单独基于DNA序列，最终诊断和亚分类对VWD进行了医学”，并作为其他遗传疾病的有用范例。该计划还将重点放在通过直接识别有助于静脉血栓（VTE）疾病敏感性的新型基因人类VTE患者的基因组序列分析，以及广泛的整个基因组诱变筛查实验室小鼠中的血栓形成抑制基因。最后，在“床头”到“长凳”翻译中，实验室有扩大了对稀有遗传出血障碍的研究，将因素V和VIII的缺乏融合到探索细胞运输途径的基本功能，导致意外见解到分子先天性肿瘤性贫血II的发病机理和血浆胆固醇水平的调节。这些发现现在从“长凳”回到“床边”，有可能提供改进相关疾病的诊断和治疗。综上所述，该研究计划将采用尖端遗传和基因组技术识别关键基因改变了许多多个风险和严重性血液和心脏病，以及有关可能引发的基本生物过程的信息未来新颖方法的基础工作来诊断和治疗这些疾病。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of plasma von Willebrand factor.

DOI：
10.12688/f1000research.13056.1
发表时间：
2018
期刊：
F1000Research
影响因子：
0
作者：
Desch KC
通讯作者：
Desch KC

Identification of secreted proteins by comparison of protein abundance in conditioned media and cell lysates.

DOI：
10.1016/j.ab.2022.114846
发表时间：
2022-10-15
期刊：
Analytical biochemistry
影响因子：
2.9
作者：
通讯作者：

Genome Editing and Hematologic Malignancy.

基因组编辑和血液恶性肿瘤。

DOI：
10.1146/annurev-med-052318-100741
发表时间：
2020
期刊：
Annual review of medicine
影响因子：
10.5
作者：
Emmer,BrianT;Ginsburg,David
通讯作者：
Ginsburg,David

Whole exome sequencing of ENU-induced thrombosis modifier mutations in the mouse.

DOI：
10.1371/journal.pgen.1007658
发表时间：
2018-09
期刊：
PLoS genetics
影响因子：
4.5
作者：
Tomberg K;Westrick RJ;Kotnik EN;Cleuren AC;Siemieniak DR;Zhu G;Saunders TL;Ginsburg D
通讯作者：
Ginsburg D

Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.