INTERACTION OF HOMOCYSTEINE AND LP(A) IN VIVO

同型半胱氨酸和 LP(A) 在体内的相互作用

• 批准号: 2750639
• 负责人: RICHARD M LAWN
• 金额: $ 28.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2750639
• 关键词: atherosclerotic plaque; blood chemistry; blood lipoprotein; cardiovascular disorder chemotherapy; chemical binding; cystathionine beta synthase; disease /disorder model; disease /disorder proneness /risk; drug screening /evaluation; enzyme deficiency; fibrin; homocysteine; human tissue; intermolecular interaction; laboratory mouse; model design /development; molecular pathology; nonhuman therapy evaluation; thrombosis

DESCRIPTION (Adapted from applicant's abstract) Atherosclerosis and thrombosis are the major causes of death in Western civilization. They are complex syndromes with numerous environmental and inherited risk factors which interact in ways that are poorly understood. Elevated blood levels of homocysteine and the lipoprotein Lp(a) have both been shown to be independent risk factors for vascular disease. There is recent in vitro evidence to suggest that homocysteine and Lp(a) may act in ways which potentiate their delerious activity. Exploration of this interaction could lead to means to recognize and prevent the consequences of moderate or severe elevation in these risk factors. Homocysteine has been shown to increase the affinity of binding of Lp(a) to fibrin. Fibrin binding, and the subsequent inhibition of plasminogen activation and clot lysis are key pathogenic activities of Lp(a), contributing to atherosclerosis, cerebrovascular stroke and other vascular abnormalities. The investigators propose examine the nature of the homocysteine/Lp(a) fibrin interaction in vitro and in human plasma using biochemical and biophysical techniques, with wild type and mutated forms of Lp(a). Genetically manipulated mouse strains provide an animal model system in which to rigorously test this interaction in vivo. The applicants will use apo(a) transgenic mice and cystathionine Beta-synthase deficient mice to create a manipulatable, small animal model of elevated homocysteine and Lp(a). The mice will be utilized in several assays of atherosclerosis and thrombosis, to test hopotheses concerning their synergistic pathological interactions which include the ability of homocysteine to modulate fibrin binding of Lp(a), interfere with clot lysis, and drive atherogenesis by altering growth factor activation in the vessel wall. The interaction of homocysteine and Lp(a) will also be explored in the settings of induced systemic thrombosis and of venous clot lysis. Finally, these animal models will be utilized to test the efficacy of drugs designed to reduce the concentration of homocysteine, alter the activity of Lp(a), improve endothelial function, or otherwise modulate pathogenic events triggered by these two important risk factors for cardiovascular disease. (End of Abstract)

描述 （改编自申请人的摘要）动脉粥样硬化和血栓形成是 西方文明的主要死亡原因。 它们是复杂的综合征 与许多环境和继承的风险因素相互作用 理解的方式。 同型半胱氨酸的血液水平升高 脂蛋白LP（a）都被证明是独立的危险因素 用于血管疾病。 最近有体外证据表明 同型半胱氨酸和LP（a）可能以增强其精神的方式行动 活动。 对这种互动的探索可能导致识别 并防止这些风险中等或重度高程的后果 因素。 同型半胱氨酸已被证明会增加LP（a）结合的亲和力 纤维蛋白。 纤维蛋白结合，随后抑制纤溶酶原 激活和凝块溶解是LP（A）的关键致病活性 导致动脉粥样硬化，脑血管中风和其他血管 异常。 调查人员建议检查 同型半胱氨酸/LP（A）在体外和人血浆中使用纤维蛋白相互作用 生化和生物物理技术，具有野生型和突变形式 LP（A）。 遗传操纵的小鼠菌株在 在体内严格测试这种相互作用。 申请人将使用 APO（A）转基因小鼠和胱硫唑β-合成酶缺乏小鼠 创建一个可操纵的小动物模型，以升高同型半胱氨酸和 LP（A）。 小鼠将用于几种动脉粥样硬化和 血栓形成，测试有关其协同病理学 相互作用，包括同型半胱氨酸调节纤维蛋白的能力 LP（A）的结合，干扰凝块溶解，并通过 改变血管壁的生长因子激活。 相互作用 同型半胱氨酸和LP（a）也将在诱导的设置中探索 全身性血栓形成和静脉血块裂解。 最后，这些动物模型 将利用用于测试旨在减少该药物的功效 同型半胱氨酸的浓度，改变LP（a）的活性，改善 内皮功能，或以其他方式调节由 这两个心血管疾病的重要危险因素。 （结束 抽象的）