AT1 RECEPTOR CONTROL IN CHRONIC HYPERTENSION ATTENUATION

慢性高血压衰减中的 AT1 受体控制

• 批准号: 6722754
• 负责人: Mohan K. Raizada
• 金额: $ 4.27万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722754
• 关键词: angiotensin /renin /aldosterone hypertension; angiotensin II; angiotensin receptor; antisense nucleic acid; biotechnology; gene targeting; gene therapy; genetic regulation; genetically modified animals; hypertension; laboratory mouse; laboratory rat; nonhuman therapy evaluation; renin angiotensin system; spontaneous hypertensive rat; tissue /cell culture; transfection; vasomotion

DESCRIPTION (Adapted from Applicant's Abstract): Hypertension is a complex pathological state that is manifested as chronic blood pressure. It affects all vital organs, and is a major risk for many cardiovascular diseases. Overwhelming evidence has established that an altered renin-angiotensin system (RAS) plays a key role in the development and establishment of hypertension. Thus, traditional pharmacological agents that influence the RAS are effective antihypertensive therapy. In spite of its success, the traditional therapy is not a cure of hypertension and suffers from many side effects and compliance issues. As a result, the investigators set out to investigate the possibility of genetic targeting of the RAS as a means to control hypertension on a long-term basis. Their studies have established that a single dose of a retroviral vector containing angiotensin II type I receptors antisense (AT1R-AS) or angiotensin-converting enzyme antisense (ACE-AS) prevents hypertension for life in the spontaneously hypertensive rat (SHR). These observations led them to conclude that the antisense therapy (AS) is conceptually sound, technically feasible, and may hold promise for cure of hypertension. The objective during this grant period is to test an overall hypothesis that AS targeting to regulate the expression of the RAS would prevent the development of hypertension on a permanent basis as a result of genomic integration of AT1R-AS or ACE-AS. If successful, a regulatable system of the AS, and thus antihypertensive actions, could be controlled on demand. The aims of the study are: 1) investigate the mechanism of a long-term protection against hypertension by the AT1R-AS gene therapy; 2) investigate involvement of central angiotensin in antihypertensive actions of AT1R-AS gene therapy; 3) investigate the role of tissue RAS in hypertension, and 4) establish long-term reversal of hypertension by the use of a novel viral vector system. State-of-the-art techniques of gene transfer, viral vectors, and molecular biology will be used to accomplish these aims. The investigators believe that this research proposal is low risk in nature and will have high impact in the development of strategies for long-term control of hypertension. The outcome of this research has a potential to be immediately adapted for the treatment of human hypertension and other cardiovascular diseases.

描述（改编自申请人的摘要）：高血压是一个复杂的 病理性状态表现为慢性血压。它会影响一切 重要器官，是许多心血管疾病的主要风险。 压倒性的证据表明，肾素 - 血管紧张素系统发生了变化 （RAS）在高血压的发展和建立中起关键作用。 因此，影响RA的传统药理剂是有效的 降压治疗。尽管成功，但传统疗法是 没有治愈高血压的治疗，并且患有许多副作用和合规性 问题。结果，调查人员着手研究可能性 RA的遗传靶向作为控制高血压的手段 长期基础。他们的研究表明，一剂 逆转录病毒载体含有血管紧张素II型受体反义 （AT1R-AS）或血管紧张素转换酶反义（ACE-AS）阻止 自发性高血压大鼠（SHR）中生命的高血压。这些 观察结果使他们得出结论，反义疗法（AS）为 从概念上讲是合理的，在技术上可行，并且可能有望治愈 高血压。该赠款期间的目的是测试总体 假设作为调节Ras表达的目标 由于 AT1R-AS或ACE-AS的基因组整合。如果成功，则可以调节系统 可以根据需要控制AS，因此可以控制降压行动。 该研究的目的是：1）研究长期的机制 保护AT1R-AS基因疗法的高血压； 2）调查 中央血管紧张素参与AT1R-AS基因的降压作用 治疗; 3）研究组织Ras在高血压中的作用，4） 通过使用新型病毒载体来建立高血压的长期逆转 系统。基因转移，病毒载体和 分子生物学将用于实现这些目标。调查人员 认为这项研究建议本质上是低风险，并且会有很高的风险 影响长期控制高血压的策略的影响。 这项研究的结果有可能立即适应 治疗人类高血压和其他心血管疾病。