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Project 4: Epigenetic Mechanisms Modulating VWF

项目 4：调节 VWF 的表观遗传机制

基本信息

批准号：
10379438
负责人：
Christopher Ng
金额：
$ 27.18万
依托单位：
VERSITI WISCONSIN, INC.
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：
2019-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379438
关键词：
5&apos Untranslated Regions ABO blood group system AVPR2 gene Affect Age Aging Binding Binding Sites Biological Assay Biology Blood Cell model ChIP-seq Code CpG Islands Data Endothelial Cells Epigenetic Process GNA12 gene General Population Genes Genetic Transcription Hematological Disease Hemorrhage Hemostatic Agents Histone Acetylation Histones Hypermethylation Individual Inflammation Interleukin-1 beta Messenger RNA Methylation MicroRNAs Modification Mutation Myocardial Infarction NFAT5 protein PF4 Gene Pathway interactions Patients Pattern Plasma Positioning Attribute Proteins RNA Polymerase II Regulation Reporter Reporting Research Risk Factors Role Site-Directed Mutagenesis Small Interfering RNA Stroke TNF gene Testing Thrombosis Transcriptional Regulation Transfection Variant age effect base bisulfite sequencing cytokine differential expression disease phenotype epigenetic regulation experimental study genome wide methylation histone methylation histone modification locked nucleic acid novel overexpression programs promoter release factor single-cell RNA sequencing thrombotic transcription factor transcriptome sequencing vector von Willebrand Disease von Willebrand Factor

项目摘要

PROJECT SUMMARY: PROJECT 4 (ESI) Von Willebrand factor (VWF) is an essential hemostatic protein and alterations of VWF levels are associated with bleeding and thrombosis. VWF levels < 50 IU/dL represent a risk factor for bleeding while VWF levels < 30 IU/dL define Willebrand disease (VWD) and are often associated with mutations in the VWF gene. Alternatively, high levels of VWF are associated with thrombotic conditions such as myocardial infarction and stroke. The wide distribution of VWF levels in the general population indicates that there are multiple factors that regulate VWF levels. To date, major modifiers such as the ABO blood group and specific variants in genes implicated in VWF release (STXBP1, GNA12) or clearance (LRP1, AVPR2, ACE) account for only 30-40% of the known variation. The objective of this proposal is to identify alternative mechanisms that regulate VWF levels. Our central hypothesis is that specific transcriptional and epigenetic mechanisms in endothelial cells are critical determinants of VWF levels. The hypothesis is based on recent reports and our preliminary data that microRNAs levels (miRs), transcription factors, and epigenetic mechanisms can all modify VWF levels. We are uniquely positioned to test this hypothesis using our primary patient-derived blood outgrowth endothelial cells (BOECs) that replicate accurately the disease phenotype. We will test our hypothesis via the following three aims, (1) Determination of transcriptional mechanisms that affect VWF expression in BOECs, (2) Determination of the contribution of methylation and histone-acetylation status of VWF on VWF expression from BOECs and (3) Determination of the role of transcriptional and epigenetic mechanisms on VWF levels in aging. Our preliminary data and our expertise in BOEC models positions us well to carry out these proposed research aims. Successful completion of these aims will (1) confirm novel transcriptional regulators of VWF in low VWF BOECs, such as miR-24 and TCF4, (2) confirm the regulatory role of epigenetic modifiers, such as VWF promoter methylation and histone acetylation, in determining VWF levels, and (3) demonstrate novel transcriptional and epigenetic regulation that may explain the effects of aging on VWF levels. In addition, our un-biased RNA sequencing, methylation arrays, and microRNA arrays may also identify additional targets for VWF regulation. Globally, by evaluating the role of transcriptional and epigenetic regulators on VWF levels it is anticipated that we will identify novel mechanisms of VWF expression and function. Such results are significant as they are expected to advance the understanding of how modifiers outside of the VWF coding region can influence VWF levels and represent novel pathways of VWF regulation that have previously not been well examined.

项目总结：项目4 （esi）