Molecular Medicine Approaches to the Treatment of Vascular Disease

治疗血管疾病的分子医学方法

• 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
• 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

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型的分子医学方法来治疗冠状动脉狭窄。经皮式冠状动脉血管成形术已成为冠状动脉血运重建的流行技术。每年有超过150万个程序。尽管介入心脏病学领域的技术进步，但冠状动脉支架是最重要的，但再狭窄仍然是降低长期疗效的问题。介入冠状动脉成形术或金属支架植入后的再狭窄均由血管平滑肌细胞增殖。已知细胞内钙浓度可以控制非增殖的血管平滑肌细胞中的基因表达。因此，毫不奇怪，平滑肌细胞增殖与钙调节蛋白的变化有关。我们最近表明，在血管狭窄期间，关键的细胞内钙调节蛋白（即SERCA2A）降低。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。 特定目的1：假设：SERCA2A可以治疗用来降低血管狭窄的程度。方法：我们将使用腺病毒载体过度表达SERCA2A体内。 以下参数将作为定量终点：a）颈动脉动脉的形态特征，b）炎性细胞浸润，c）血管平滑肌细胞的表型，d）血管壁内凋亡的程度，E）血管壁内细胞周期蛋白质的变化。