Beta1 Adrenoreceptor Antisense Control in Heart Failure

心力衰竭中的 Beta1 肾上腺素受体反义控制

• 批准号: 6436325
• 负责人: MICHAEL. IAN PHILLIPS
• 金额: $ 29万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6436325
• 关键词: antisense nucleic acid; beta adrenergic receptor; beta antiadrenergic agent; calcium transporting ATPase; drug screening /evaluation; genetically modified animals; heart disorder chemotherapy; heart failure; heart rate; laboratory mouse; laboratory rat; nonhuman therapy evaluation; pharmacokinetics; sarcoplasmic reticulum; ventricular hypertrophy

DESCRIPTION (provided by applicant): B-blockers have long been used as the first line of treatment in hypertension. The majority of B-blockers are both B1 and B2-active. Although there are B1 and B2-selective drugs, they are not B1 or B2-specific. We have developed a novel approach to B-blockade using antisense technology to produce a high-specific non-toxic, long-acting inhibitor of B1-adrenoreceptors (B1-AR). The antisense oligonucleotide to B1 mRNA (B1-AS-ODN) reduces cardiac output without a reduction in heart rate. We hypothesize that this difference is due to the specific inhibition of B1-receptors. Since clinical trials have shown improved cardiac function in heart failure patients with B-blockers, we propose to use the B1-AS-ODN in comparison to current B-blockers to study the mechanisms of the beneficial effects. AIM 1: To investigate the underlying mechanisms by which 1-AS-ODN decreases cardiac contractility but not heart rate, we will test three alternative hypotheses: 1) that the B1-AR have a higher receptor reserve for controlling heart rate, 2) the B2-receptors play a more important role in heart rate regulation than B1-AR, 3) pacemaker cells in the heart may take up B1-AS less efficiently than cardiomyocytes. AIM 2: To elucidate whether a reduction in heart rate is necessary for improving cardiac performance in heart failure by beta-blockade, we will test by comparing B1-AS-ODN to B1-selective blockers on ameliorating cardiac dysfunction induced by aortic banding. AIM 3: To study the long-term protective effect of B1-AS-ODN in the prevention and or reversal of LVH and remodeling, we will use transgenic mice over expressing cardiac B1-AR (B1TG4) and test the long-term effects of the AS. Also, we will test rats with aortic banding. In view of the potential use for B-blockers in therapy for heart failure, myocardial infarction and sudden cardiac death, this proposal offer a novel approach, which would have a high impact and low risk.

描述（由申请人提供）：B街区长期以来一直被用作 高血压的第一道治疗。大多数B街区都是B1 和B2活性。尽管有B1和B2选择性药物，但它们不是B1或 特定于B2。我们已经使用反义开发了一种新型的B块方法 产生高特异性无毒的长效抑制剂的技术 B1-肾上腺受体（B1-AR）。反义寡核苷酸至B1 mRNA （B1-As-ODN）减少心脏输出而不会降低心率。我们 假设这种差异是由于对 B1受体。由于临床试验已显示出改善的心脏功能 心力衰竭患者患有B阻滞剂，我们建议在 与当前的B建筑物进行比较，以研究有益的机制 效果。 目的1：研究1-AS-ODN降低的基本机制 心脏收缩性但不是心率，我们将测试三个替代方案 假设：1）B1-AR具有较高的控制受体储备 心率，2）B2受体在心率上起着更重要的作用 调节比b1-ar，3）心脏中的起搏器细胞可能占B1- 比心肌细胞有效。 目标2：阐明是否需要降低心率 通过Beta-Blockade提高心力衰竭的心脏表现，我们将测试 通过将B1-AS-ODN与B1选择性阻滞剂进行比较，以改善心脏 主动脉带引起的功能障碍。 目标3：研究B1-AS-ODN在预防中的长期保护作用 或LVH和重塑的逆转，我们将使用转基因小鼠 表达心脏B1-AR（B1TG4）并测试AS的长期影响。 另外，我们将用主动脉束带测试大鼠。 鉴于对B阻滞剂在心力衰竭治疗中的潜在用途， 心肌梗塞和突然心脏死亡，该提案提供了一本小说 方法，这将具有很高的影响和低风险。