Molecular Medicine Approaches to the Treatment of Vascular Disease

治疗血管疾病的分子医学方法

基本信息

批准号：
7395205
负责人：
Judith K Gwathmey
金额：
$ 67.01万
依托单位：
GWATHMEY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7395205
关键词：
Adenovirus Vector Animal Model Apoptosis Atherosclerosis Blood Vessels Calcium Cardiology Carotid Arteries Cell Cycle Proteins Cell Proliferation Cells Characteristics Coronary Coronary Stenosis Coronary artery End Point Family suidae Funding Gene Expression Goals Imaging Techniques Infiltration Inflammatory Investigational New Drug Application Metals Modeling Molecular Medicine Oryctolagus cuniculus Pathway interactions Percutaneous Transluminal Coronary Angioplasty Personal Satisfaction Pharmaceutical Preparations Phase Phenotype Positioning Attribute Prevention Procedures Proliferating Proteins Protocols documentation Regulation Rodent Model SERCA2a Smooth Muscle Myocytes Stenosis Stents Sus scrofa Techniques Therapeutic Therapeutic Intervention Toxicology Transgenes Vascular Diseases Vascular remodeling coronary angioplasty implantation in vivo novel research study restenosis vascular smooth muscle cell proliferation vector

项目摘要

DESCRIPTION (provided by applicant): We plan to develop a novel molecular medicine approach for the treatment of coronary stenosis. Percutaneous transluminal coronary angioplasty has become the prevailing technique for coronary revascularization. There are over 1.5 million procedures every year. Despite technical advances in the field of interventional cardiology, of which coronary stenting has been the most significant, restenosis remains a problem diminishing long-term efficacy. Restenosis after interventional coronary angioplasty or metal stent implantation are both due to proliferation of vascular smooth muscle cells. Intracellular calcium concentration is known to control gene expression in non- proliferating vascular smooth muscle cells. It is therefore, not surprising that smooth muscle cell proliferation has been associated with changes in calcium modulating proteins. We have recently shown that a key intracellular calcium modulating protein, i.e., SERCA2a, is reduced during vascular stenosis. We hypothesize that we can regulate vascular smooth muscle cell proliferation in a therapeutic setting through regulation of SERCA2a expression levels. Specific Aim 1: Hypothesis: SERCA2a can be used therapeutically to reduce the extent of vessel stenosis. Approach: We will over-express SERCA2a in vivo using an adenoviral vector. The following parameters will serve as quantitative end-points: a) Morphological characteristics of carotid arteries, b) Inflammatory cell infiltration, c) Phenotype of vascular smooth muscle cells, d) Extent of apoptosis within the vessel wall, e) Changes in cell cycle proteins within the vessel wall.

描述（由申请人提供）：我们计划开发一种新的分子医学方法来治疗冠状动脉狭窄。经皮冠状动脉腔内成形术已成为冠状动脉血运重建的主流技术。每年有超过 150 万例手术。尽管介入心脏病学领域取得了技术进步（其中冠状动脉支架置入术最为重要），但再狭窄仍然是一个降低长期疗效的问题。冠状动脉介入成形术或金属支架植入后的再狭窄都是由于血管平滑肌细胞的增殖所致。已知细胞内钙浓度控制非增殖血管平滑肌细胞中的基因表达。因此，平滑肌细胞增殖与钙调节蛋白的变化有关也就不足为奇了。我们最近发现，一种关键的细胞内钙调节蛋白，即 SERCA2a，在血管狭窄期间会减少。我们假设我们可以通过调节 SERCA2a 表达水平来调节治疗环境中的血管平滑肌细胞增殖。具体目标 1：假设：SERCA2a 可用于治疗以减少血管狭窄程度。方法：我们将使用腺病毒载体在体内过度表达 SERCA2a。以下参数将作为定量终点：a) 颈动脉的形态特征，b) 炎症细胞浸润，c) 血管平滑肌细胞的表型，d) 血管壁内细胞凋亡的程度，e) 细胞周期的变化血管壁内的蛋白质。