REGULATION OF AT1R ANTISENSE IN CONTROL OF HYPERTENSION

AT1R 反义蛋白的调节控制高血压

• 批准号: 6548640
• 负责人: SHARON C FRANCIS
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6548640
• 关键词: Retroviridae; angiotensin /renin /aldosterone hypertension; angiotensin receptor; antisense nucleic acid; disease /disorder model; gene therapy; genetically modified animals; laboratory mouse; laboratory rat; spontaneous hypertensive rat; tetracyclines; transfection /expression vector; vascular smooth muscle

Hypertension is a major risk factor for cardiovascular disease and has emerged as a tremendous economical and emotional burden on society. Thus, it is imperative that a permanent treatment and cure for this disease is discovered. We have developed a model that uses a retroviral-mediated gene delivery system to deliver antisense to the type 1 angiotensin receptor (AT1R-AS) to 5-day old rats. This delivery has profound beneficial effects on blood pressure and cardiac and renal pathophysiology in both the spontaneous hypertensive rat genetic model and in the chronic angiotensin II acquired hypertension model. Unfortunately, this system does not address critical issues of safety and efficacy. The ability to regulate expression of the therapeutic gene is crucial, because the therapeutic window or level of AS gene that is needed may vary during the course of the disease or between hypertensive individuals. Additionally, in cases of unanticipated side- effects it will be important to switch off expression of the AS gene. The purpose of this proposal then, is to develop a regulatable system for AT1R-AS wherein issues of safety and efficacy can be tested. We propose to infect two animal models of hypertension (genetic and acquired) with retroviral vectors harboring AT1R-AS under a tetracycline-regulatable promoter We will use these models to test the hypothesis that doxycycline, (Dox) a potent tetracycline derivative, can induce AT1R-AS expression and thus regulate its subsequent antihypertensive effects. Thus, specific aims of this research program will be as follows: 1. To characterize the efficiency and efficacy of RevTRE-AT1R-AS In vitro, 2. To determine the expression potential, physiological and cellular consequences of Dox-controlled AT1R-AS expression. 3. To test the efficacy of the Dox AT1R-AS system in chronic Ang II infusion model of hypertension.This project will have a profound impact on the way to treat and control hypertension and other cardiovascular diseases.

高血压是心血管疾病的主要危险因素，并且已经成为社会上的巨大经济和情感负担。因此，必须发现永久治疗和治愈该疾病。我们已经开发了一种模型，该模型使用逆转录病毒介导的基因递送系统将反义递送至1型血管紧张素受体（AT1R-AS）至5天大的大鼠。在自发性高血压大鼠遗传模型和慢性血管紧张素II获得的高血压模型中，这种递送对血压以及心脏和肾脏病理生理的有益影响。不幸的是，该系统没有解决安全和功效的关键问题。调节治疗基因表达的能力至关重要，因为在疾病过程中或高血压个体之间，治疗窗口或所需的AS基因水平可能会有所不同。此外，在意外副作用的情况下，关闭AS基因表达非常重要。因此，该提案的目的是为AT1R-AS开发可调节的系统，其中可以测试安全性和功效问题。我们建议通过在四环素 - 可调节的启动子下载有AT1R-AS的逆转录病毒载体的两种动物模型（遗传和获得），我们将使用这些模型来测试强力霉素的假设（（DOX），（DOX）一种有效的Tetracycline衍生物可以诱导AT1R-AS的表达并施加效果。因此，该研究计划的具体目的将如下：1。表征Revtre-At1r-As在体外的效率和功效，2。确定DOX控制的AT1R-AS表达的表达潜力，生理和细胞后果。 3。测试DOX AT1R-AS系统在高血压的慢性ANG II输注模型中的功效。该项目将对治疗和控制高血压和其他心血管疾病的方式产生深远的影响。