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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.

项目总结

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.

血浆von Willebrand因子的调节。

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.