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）分化是血管生成和发育过程中非常重要的过程。 SMC 表型的改变在血管生成的进展中发挥着重要作用，这一点已得到广泛认可。几种主要的心血管疾病状态，包括动脉粥样硬化、高血压和再狭窄。在之前的资助期间，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类主动脉 SMC 的染色质结构和转录因子结合。我们的工作导致了以前未被识别的 SMC 选择性蛋白的鉴定，以及调节 SMC 收缩性和血压的遗传机制以及新的转录调节 SMC 特异性基因表达的机制。使用我们最近发现的质谱方法 SMC 选择性甲基转移酶 PRDM6 作为心肌因子相互作用蛋白并进行细胞培养体内数据表明 PRDM6 是维持 SMC 分化和血压所必需的。重要的是，最近的人类遗传学研究描述了导致导管未闭的 PRDM6 编码突变动脉粥样硬化和 GWAS 已经确定了 PRDM 中与血压调节和颅内动脉粥样硬化相关的位点。动脉瘤。在目标 1 中，我们将确定调节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完全未知，在 Aim2 中我们将使用全基因组方法来直接识别 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我们的条件性 SMC 特异性 PRDM6 敲除小鼠进行体内实验。我们还与以下机构建立了合作关系北卡罗来纳大学临床心血管研究小组开始研究两者之间的相关性 PRDM6基因型与当地人群高血压之间的关系。

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）

Transcriptional and posttranscriptional regulation of the SMC-selective blood pressure-associated gene, ARHGAP42.

SMC 选择性血压相关基因 ARHGAP42 的转录和转录后调控。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Mangum, Kevin D;Freeman, Emily J;Magin, Justin C;Taylor, Joan M;Mack, Christopher P
通讯作者：
Mack, Christopher P

The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension.

平滑肌选择性 RhoGAP GRAF3 是血管张力和高血压的关键调节因子。

DOI：
发表时间：
2013
期刊：
影响因子：
16.6
作者：
Bai, Xue;Lenhart, Kaitlin C;Bird, Kim E;Suen, Alisa A;Rojas, Mauricio;Kakoki, Masao;Li, Feng;Smithies, Oliver;Mack, Christopher P;Taylor, Joan M
通讯作者：
Taylor, Joan M

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

Rho 通路中的药物靶标及其对血压控制的治疗前景。

DOI：
发表时间：
2019-01
期刊：
影响因子：
13.5
作者：
Dee, Rachel A;Mangum, Kevin D;Bai, Xue;Mack, Christopher P;Taylor, Joan M
通讯作者：
Taylor, Joan M

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

Prdm6 通过促进动脉导管平滑肌细胞的特性和收缩力来驱动动脉导管闭合。

DOI：
发表时间：
2023-03-08
期刊：
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

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

抑制体内透明福明信号传导会损害心血管发育并改变平滑肌细胞表型。