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-阻滞剂长期以来一直被用作 高血压的一线治疗。大多数 B 阻滞剂都是 B1 和B2-活性。虽然有B1和B2选择性药物，但它们不是B1或B2 B2 专用。我们开发了一种使用反义 B 阻断的新方法 技术生产高特异性、无毒、长效的抑制剂 B1-肾上腺素受体（B1-AR）。 B1 mRNA 的反义寡核苷酸 (B1-AS-ODN) 可减少心输出量而不降低心率。我们 假设这种差异是由于特异性抑制 B1-受体。由于临床试验表明心脏功能得到改善 对于使用 B 受体阻滞剂的心力衰竭患者，我们建议在以下情况中使用 B1-AS-ODN： 与目前的 B 受体阻滞剂进行比较，以研究其有益机制 影响。 目标 1：研究 1-AS-ODN 降低的潜在机制 心肌收缩力但不是心率，我们将测试三种替代方案 假设：1）B1-AR具有更高的受体储备来控制 心率，2) B2 受体在心率中发挥更重要的作用 调节作用比 B1-AR 强，3) 心脏起搏细胞对 B1-AS 的吸收可能较少 比心肌细胞有效。 目标 2：阐明是否有必要降低心率 通过β-阻断改善心力衰竭的心脏功能，我们将测试 通过比较 B1-AS-ODN 与 B1 选择性阻滞剂对改善心脏功能的影响 主动脉束带引起的功能障碍。 目的3：研究B1-AS-ODN在预防中的长期保护作用 和/或逆转 LVH 和重塑，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。 此外，我们还将测试带有主动脉束带的老鼠。 鉴于 B 受体阻滞剂在心力衰竭治疗中的潜在用途， 心肌梗塞和心源性猝死，该提案提供了一种新颖的方法 方法，这将产生高影响和低风险。