CONTROL OF LP(A) IN VITRO AND IN TRANSGENIC MICE

LP(A) 的体外和转基因小鼠的控制

• 批准号: 2688207
• 负责人: RICHARD M LAWN
• 金额: $ 10.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-18 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2688207
• 关键词: apolipoproteins; atherosclerosis; blood chemistry; blood lipoprotein; cytokine; dietary lipid; estrogens; gene expression; genetic promoter element; genetic regulation; genetically modified animals; hormone regulation /control mechanism; human subject; laboratory mouse; molecular cloning; molecular pathology; nutrition related tag; plasma; sex hormones; tamoxifen

DESCRIPTION (Adapted from Investigator's Abstract): This is an application for competitive renewal of a grant to study control of expression of the atherogenic lipoprotein, lipoprotein(a) [Lp(a)]. Plasma levels of Lp(a) correlate generally with propensity for vascular diseases (myocardial infarction, re-stenosis, and stroke). The applicant proposes to utilize both in vitro and in vivo (transgenic model) approaches to delineate how the 1000-fold variation in plasma levels of Lp(a) in humans, which appears to be at least partially genetically determined, is accomplished. The applicant will examine the mechanism by which sex hormones and dietary fats may influence expression of Lp(a), principally by studying their interactions with polymorphic flanking sequences in the human apo(a) gene. The proposal consists of three Specific Aims. First, having already isolated 1400 base pairs of proximal promoter region, the investigators will clone additional upstream sequences in order to identify the hormone and cytokine response elements. Second, control of apo(a) expression will be assessed in vivo by constructing transgenic mice that harbor apo(a) constructs bearing or lacking specific control elements or regions. Third, the applicant will employ transgenic mouse models to test therapeutic modalities, such as estrogen and tamoxifen, which are designed to suppress expression of apo(a).

描述（根据调查员的摘要改编）：这是一个应用程序 授予授予的竞争性更新，以研究对表达的控制 动脉粥样硬化脂蛋白，脂蛋白（A）[LP（A）]。 血浆LP的水平（a） 通常与血管疾病倾向（心肌 梗塞，重新发生和中风）。 申请人建议使用 体外和体内（转基因模型）的方法，用于描述如何 人类的Lp（a）等离子体水平的1000倍变化，这似乎是 至少部分遗传确定，完成了。 申请人 将检查性激素和饮食脂肪的机制 影响LP（a）的表达，主要是通过研究其相互作用 与人apo（a）基因中的多态性侧翼序列。 该提案包括三个具体目标。 首先，已经有了 孤立的1400个基对近端启动子区域，研究人员将 克隆其他上游序列，以识别激素和 细胞因子反应元素。 其次，对Apo（a）表达式的控制将是 通过构造含有apo的转基因小鼠（a）的转基因小鼠进行评估 构造或缺乏特定的控制元素或区域的结构。 第三， 申请人将采用转基因小鼠模型来测试治疗 雌激素和他莫昔芬等模态，旨在抑制 apo（a）的表达。