Novel Molecular Regulators of Vascular Calcification

血管钙化的新型分子调节剂

• 批准号: 10605099
• 负责人: Sujin Lee
• 金额: $ 7.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605099
• 关键词: Aorta; Arylsulfatases; Atherosclerosis; Automobile Driving; Bioinformatics; Biological Assay; Biology; Blood Vessels; Bone Development; Bone Morphogenetic Proteins; Cardiovascular Diseases; Cell physiology; Cells; Cellular Assay; Code; Cohort Studies; Communication; Coronary; Coronary Arteriosclerosis; Coronary artery; Cultured Cells; Cytosol; Data; Disease; Esters; Event; Experimental Models; Family; Fellowship; Focal Adhesion Kinase 1; Funding; Genes; Genomics; Goals; HDAC4 gene; HDAC5 gene; HDAC9 gene; Histone Deacetylase; In Vitro; Individual; Knockout Mice; Laboratories; Leadership; Mediating; Mentorship; Methods; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; Nuclear; Osteogenesis; Pathogenesis; Pathology; Peripheral arterial disease; Phenotype; Phosphorylation; Play; Prevention; Process; Protein Family; Proteins; Regulation; Research; Risk Factors; Role; Scientist; Signal Pathway; Signaling Protein; Single Nucleotide Polymorphism; Small Interfering RNA; Smooth Muscle Myocytes; Stroke; Sulfatases; Sulfate; Surgeon; Testing; United States National Institutes of Health; Variant; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; X Chromosome; abdominal aorta; adenoviral mediated; calcification; cardiovascular risk factor; career; cartilage development; coronary artery calcification; experimental study; genome wide association study; genome-wide; in vivo; inhibitor; insight; kinase inhibitor; knock-down; mRNA Expression; member; mortality; mouse model; new therapeutic target; novel; osteogenic; overexpression; pharmacologic; prevent; programs; skills; targeted treatment; transcription factor

PROJECT SUMMARY Atherosclerotic disease is characterized by intimal vascular calcification, which is an independent and potent risk factor for morbidity and mortality in coronary artery disease, stroke, and aortic pathologies. Vascular calcification is an active cell-mediated process that involves the phenotypic switch of vascular smooth muscle cells (VSMC) from contractile to osteogenic cells. Understanding the molecular mechanisms driving vascular calcification is critical for developing targeted therapies. In our lab, we have identified novel single nucleotide polymorphisms (SNPs) in the arylsulfatase E (ARSE) locus on the X chromosome that are associated with coronary artery calcification. Our preliminary data demonstrate that adenovirus-mediated overexpression of ARSE in VSMCs leads to increased calcification and that conversely, reduced expression of ARSE with siRNA prevents calcification of VSMCs. We have identified SULF1, a protein related to ARSE in the same family of sulfatases, as having similar effects on vascular calcification as that demonstrated in our in vitro studies for ARSE. Based on our previous studies, we have also identified histone deacetylase 4 and 5 (HDAC4/5) to be important regulators of vascular calcification, mediated by subcellular localization of HDAC4/5 in the cytosol through phosphorylation by focal adhesion kinase (FAK). The goal of this project is to perform in vitro, ex vivo, and in vivo studies to test the hypothesis that ARSE/SULF1 and HDAC4/5 are important and novel determinants of vascular calcification that induce the phenotypic switch of VSMCs to osteogenic cells. Overall, my aim is to unravel novel molecular mechanisms underlying VSMC function and calcification that contribute to the pathogenesis of atherosclerotic cardiovascular disease. Through world-class didactic opportunities and close mentorship from experts in the field of vascular biology and genomics, I will complete this project having gained valuable skills in bioinformatics, in vitro cellular assays modeling vascular disease, in vivo mouse model experiments, scientific communication and laboratory leadership. By the end of the fellowship, I will have gained skills necessary to develop my own research program and ultimately launch my own career as an NIH-funded vascular surgeon scientist.

项目总结 动脉粥样硬化性疾病的特征是内膜血管钙化，这是一种 冠状动脉疾病、中风、 和大动脉病变。血管钙化是一个活跃的细胞介导的过程，涉及 血管平滑肌细胞(VSMC)从收缩细胞到成骨细胞的表型转换。 了解驱动血管钙化的分子机制对发展至关重要 有针对性的治疗。在我们的实验室中，我们发现了新的单核苷酸多态(SNPs) 在X染色体上与冠状动脉相关的芳基硫酸酯酶E(HASH)基因座 动脉钙化。我们的初步数据表明，腺病毒介导的过度表达 HASH在VSMC中的表达导致钙化增加，反之，表达减少 含有siRNA的HASH可防止VSMCs的钙化。我们已经鉴定出一种与SULF1相关的蛋白质 在相同的硫酸酯酶家族中，对血管钙化的影响类似于 这在我们对屁股的体外研究中得到了证实。在我们之前的研究基础上，我们还 组蛋白脱乙酰酶4和5(HDAC4/5)是重要的血管调节因子 胞浆中HDAC4/5的亚细胞定位介导的钙化 粘着斑激酶(FAK)的磷酸化。这个项目的目标是在体外进行，例如 活体和体内研究，以检验HASH/SULF1和HDAC4/5重要的假设 和诱导VSMC表型转换的血管钙化的新决定因素 成骨细胞。总的来说，我的目标是揭开VSMC背后的新的分子机制 动脉粥样硬化性心血管疾病发病机制中的功能和钙化 疾病。通过世界级的教学机会和来自 在血管生物学和基因组学领域，我将完成这个项目，获得了宝贵的技能 在生物信息学中，体外细胞分析模拟血管疾病，体内小鼠模型 实验、科学交流和实验室领导。在团契结束时，我 我将获得开发我自己的研究计划并最终推出我的 他的职业生涯是美国国立卫生研究院资助的血管外科科学家。