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的技术进步，其中冠状动脉支架植入术是最重要的，再狭窄仍然是一个问题，降低了长期疗效。冠状动脉介入性血管成形术或金属支架植入术后的再狭窄都是由于血管平滑肌细胞增殖所致。细胞内钙离子浓度控制非增殖性血管平滑肌细胞的基因表达.因此，平滑肌细胞增殖与钙调节蛋白的变化有关并不奇怪。我们最近已经表明，一个关键的细胞内钙调节蛋白，即，SERCA2a在血管狭窄期间减少。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可用于治疗以降低血管狭窄程度。方法：我们将使用腺病毒载体在体内过表达SERCA2a。 以下参数将作为定量终点：a）颈动脉的形态学特征，B）炎性细胞浸润，c）血管平滑肌细胞的表型，d）血管壁内细胞凋亡的程度，e）血管壁内细胞周期蛋白的变化。