Genetic and epigenetic regulation of vascular smooth muscle cell phenotype and contractility

血管平滑肌细胞表型和收缩性的遗传和表观遗传调控

基本信息

批准号：
10412926
负责人：
Christopher P. Mack
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-02 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10412926
关键词：
Address Adult Affinity Alleles Aorta Atherosclerosis Binding Binding Sites Blood Pressure CRISPR/Cas technology Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Differentiation process Cell physiology Cells Chromatin Chromatin Structure Clinical Co-Immunoprecipitations Code Collaborations Computational Biology DOCA Data Data Set Development Differentiation Antigens Disease Enhancers Enzymes Epigenetic Process Family Funding Gene Expression Genes Genetic Genetic Transcription Genetic Variation Genetic study Genomics Genotype Goals Heritability High-Throughput Nucleotide Sequencing Human Human Genetics Hypertension Intracranial Aneurysm Introns Knock-out Knockout Mice Legal patent Maintenance Measures Mediating Methylation Methyltransferase Minor Molecular Morphology Mus Mutagenesis Mutation North Carolina Pattern Phenotype Play Population Process Proteins Rattus Regimen Regulatory Element Research Role Serum Response Factor Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Sodium Chloride Tamoxifen Tertiary Protein Structure Testing Universities Vascular Smooth Muscle Work angiogenesis base blood pressure control blood pressure regulation blood vessel development cell type chromatin modification chromatin remodeling epigenetic regulation genetic variant genome wide association study genome-wide histone methyltransferase in vivo insight knock-down mature animal mouse model myocardin new therapeutic target novel patient population restenosis transcription factor vasculogenesis

项目摘要

Summary Vascular smooth muscle cell (SMC) differentiation is a very important process during vasculogenesis and angiogenesis, and it is well recognized that alterations in SMC phenotype play a role in the progression of several prominent cardiovascular disease states including atherosclerosis, hypertension, and restenosis. During the previous funding period we used high throughput sequencing and computational biology to study chromatin structure and transcription factor binding in human aortic SMCs on a genome-wide level. Our work has led to the identification of previously unrecognized SMC-selective proteins, to the characterization of genetic mechanisms that regulate SMC contractility and blood pressure, and to novel transcription mechanisms that regulate SMC-specific gene expression. Using mass spec approaches we recently identified the SMC-selective methyltransferase, PRDM6, as a myocardin factor interacting protein and have cell culture and in vivo data that PRDM6 is required for the maintenance of SMC differentiation and blood pressure. Importantly recent human genetic study described PRDM6 coding mutations that cause patent ductus arteriosis, and GWAS have identified a locus in PRDM that was associated with BP regulation and intracranial aneurysm. In Aim 1 we will identify the transcription mechanisms and human genetic variations that regulate PRDM6 the SMC-specific expression of PRDM6. Since the mechanisms by which PRDM6 regulates gene expression are completely unknown, in Aim2 we will use genome-wide approaches to identify direct PRDM6 targets, and we will test whether PRDM6 regulates MRTF-A activity by direct methylation. In Aim 3 we will continue to evaluate the contributions of PRDM6 to the regulation of blood pressure and SMC phenotype in vivo using our conditional SMC-specific PRDM6 knockout mice. We have also established collaborations with clinical cardiovascular research teams at the University of North Carolina to begin to examine the correlation between PRDM6 genotype and hypertension in local populations.

概括血管平滑肌细胞（SMC）分化是血管生成期间非常重要的过程血管生成，人们众所周知，SMC表型的改变在进展中起作用几种突出的心血管疾病状态，包括动脉粥样硬化，高血压和再狭窄。在上一个资金期间，我们使用高通量测序和计算生物学来研究在全基因组水平上，人主动脉SMC中的染色质结构和转录因子结合。我们的工作导致了先前未识别的SMC选择蛋白的鉴定，以表征调节SMC收缩性和血压的遗传机制，并进行新的转录调节SMC特异性基因表达的机制。使用我们最近确定的质量规格方法 SMC选择性甲基转移酶PRDM6作为肌动蛋白因子相互作用，并具有细胞培养在体内数据中，维持SMC分化和血压需要PRDM6。重要的是，最近的人类遗传研究描述了引起专利管道的PRDM6编码突变 Arteriosis和GWAS已确定了PRDM中的一个基因座，该基因座与BP调节和颅内有关动脉瘤。在AIM 1中，我们将确定调节调节的转录机制和人类遗传变异 PRDM6 PRDM6的SMC特异性表达。由于PRDM6调节基因的机制表达是完全未知的，在AIM2中，我们将使用全基因组的方法来识别直接PRDM6 目标，我们将测试PRDM6是否通过直接甲基化调节MRTF-A活性。在目标3中，我们将继续评估PRDM6对血压和SMC表型调节的贡献使用条件SMC特异性PRDM6敲除小鼠的体内。我们还与北卡罗来纳大学的临床心血管研究小组开始检查相关性在局部人群中PRDM6基因型和高血压之间。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RBPJ binds to consensus and methylated cis elements within phased nucleosomes and controls gene expression in human aortic smooth muscle cells in cooperation with SRF.

RBPJ 与定相核小体内的共有元件和甲基化顺式元件结合，并与 SRF 配合控制人主动脉平滑肌细胞中的基因表达。

DOI：
10.1093/nar/gky617
发表时间：
2018
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Rozenberg,JulianM;Taylor,JoanM;Mack,ChristopherP
通讯作者：
Mack,ChristopherP

Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure.

DOI：
10.1016/j.pharmthera.2018.09.001
发表时间：
2019-01
期刊：
Pharmacology & therapeutics
影响因子：
13.5
作者：
Dee RA;Mangum KD;Bai X;Mack CP;Taylor JM
通讯作者：
Taylor JM

Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility.

DOI：
10.1172/jci.insight.163454
发表时间：
2023-03-08
期刊：
JCI INSIGHT
影响因子：
8
作者：
Zou, Meng;Mangum, Kevin D.;Magin, Justin C.;Cao, Heidi H.;Yarboro, Michael T.;Shelton, Elaine L.;Taylor, Joan M.;Reese, Jeff;Furey, Terrence S.;Mack, Christopher P.
通讯作者：
Mack, Christopher P.

A Primer on Repeated Sitting Exposure and the Cardiovascular System: Considerations for Study Design, Analysis, Interpretation, and Translation.

DOI：
10.3389/fcvm.2021.716938
发表时间：
2021
期刊：
Frontiers in cardiovascular medicine
影响因子：
3.6
作者：
Stoner L;Barone Gibbs B;Meyer ML;Fryer S;Credeur D;Paterson C;Stone K;Hanson ED;Kowalsky RJ;Horiuchi M;Mack CP;Dave G
通讯作者：
Dave G

Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype.