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Functional genetics of tissue factor in bleeding and thrombotic risk

出血和血栓风险中组织因子的功能遗传学

基本信息

批准号：
9794197
负责人：
Sol Schulman
金额：
$ 43.75万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9794197
关键词：
Address Advisory Committees Anticoagulant therapy Anticoagulants Area Award Biochemistry Biological Assay Blood Coagulation Disorders Blood Coagulation Factor Blood Vessels Blood coagulation Budgets Cell surface Cells Cellular biology Choristoma Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coagulation Process Collaborations Conflict (Psychology)Core Facility Custom Data Diagnostic Disease Disease susceptibility Disseminated Intravascular Coagulation Electron Transport Endothelium Ensure Equipment Etiology Explosion Faculty Fellowship Foundations Future Genes Genetic Genetic Models Genetic Variation Genomic approach Goals Grant Hematology Hemorrhage Hemostatic Disorders Hemostatic function Heritability Human Human Genetics Human Resources Individual Inherited Injury Institutional Review Boards International Investigation Israel Laboratories Lead Leadership Medical center Medicine Mentors Mentorship Metabolism Morbidity - disease rate Mus Myocardial Infarction Ownership Oxidation-Reduction Pathogenesis Pathologic Pathway interactions Patient Care Physicians Population Positioning Attribute Principal Investigator Prize Protein Biochemistry Proteins Protocols documentation Pulmonary Embolism Quantitative Trait Loci Readiness Reporting Research Research Activity Risk Rodent Model Scientist Secure Seminal Sickle Cell Anemia Smooth Muscle Myocytes Stroke Structure Students Testing Therapeutic Thromboembolism Thromboplastin Thrombosis Training Variant Vascular Smooth Muscle Venous Vision Vitamin K Vocational Guidance Wages Warfarin career development cell type design disorder risk functional genomics genetic approach genetic association genome-wide human population study improved in vivo induced pluripotent stem cell innovation insight intravital microscopy kindred loss of function medical schools mortality personalized medicine professor recruit senior faculty square foot stem cell differentiation ubiquitin-protein ligase

项目摘要

Project Summary/Abstract Tissue factor (TF) is the primary initiator of blood coagulation in vivo and is required to ensure hemostasis following injury. However, inappropriate TF procoagulant activity underlies substantial human suffering, including that due to myocardial infarction (MI), venous thromboembolism (VTE), stroke, and sickle cell disease. Because the cellular contribution of TF is not captured in any routine clinical assay of blood coagulation, the machinery influencing TF expression and procoagulant activity remains largely unknown. Our central hypothesis is that cellular TF and its modifiers contribute to the substantial unexplained heritability of hemostatic and thrombotic disorders, including VTE, MI, and stroke. To achieve this goal, we will intersect functional genetic and human genetic approaches to identify modifiers that contribute to TF-dependent heritability of bleeding and clotting risk. TF (“factor III”) is the only coagulation factor for which a hereditary deficiency has not been described, but in Aim 1 we will study a kindred with a bleeding diathesis in association with heterozygous TF deficiency using protein biochemistry, CRISPR-edited induced pluripotent stem cells (iPSCs) differentiated into endothelial and vascular smooth muscle cells not accessible in humans, and genetically modified mice via intravital microscopy following vascular injury; importantly, these efforts provide proof of concept that modifiers reducing TF expression by 50% can influence bleeding risk in vivo. In Aim 2, we will use an arrayed loss-of-function screen at genome-scale to identify modifiers of TF cell surface expression and procoagulant activity and intersect these findings with expression quantitative trait loci and existing population data capturing common and rare human genetic variation to identify areas of intersection, offering a generalizable strategy to use a functional screen to move beyond genetic association towards causation and mechanism. Modifiers likely contributing to TF-dependent heritability of bleeding and clotting risk will be mechanistically evaluated at scale using a custom CRISPR array and then evaluated in iPSCs, mice, and, where possible, humans. In Aim 3, we will study as a representative example one such discovery, an E3 ubiquitin ligase that strongly negatively regulates TF protein stability and procoagulant activity, employing cell biology, biochemistry, rodent models, and human genetics to mechanistically demonstrate how human genetic variation may contribute to VTE risk. Our findings will highlight the critical but clinically unmeasured contribution of cellular TF to the pathogenesis and inheritance of broadly defined hemorrhagic and thrombotic diseases. The findings will have immediate translational potential for diagnostics able to capture this risk to guide personalized treatment and suggest promise for new anticoagulant therapies with reduced bleeding risk that selectively target pathways leading to inappropriate TF procoagulant activity.

项目总结/文摘