Angiotensin Receptor Regulation By Upstream Short Open Reading Frames

上游短开放阅读框对血管紧张素受体的调节

• 批准号: 8894076
• 负责人: Willis K. Samson
• 金额: $ 72.69万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-17 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894076
• 关键词: Adverse effects; Adverse event; Amino Acids; Angiotensin II; Angiotensin Receptor; Angiotensin Type 1a Receptor; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Argipressin; Arrestins; Biology; Blood Pressure; Cardiovascular Diseases; Catecholamines; Cause of Death; Cells; Chronic; Clinical; Confocal Microscopy; Cough Headaches; DOCA; Dietary Sodium; Disease; Dizziness; Electrolyte Balance; Electrolytes; Embryo; Exons; Fluid Balance; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Goals; Growth Factor Oncogenes; Health; Homeostasis; Human; Hypertension; Hypotension; Hypovolemia; Injection of therapeutic agent; Intake; Intervention; Isotonic Exercise; Kidney; Lead; Liquid substance; Mediating; Messenger RNA; Modeling; Molecular; Open Reading Frames; Oxytocin; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phosphotransferases; Play; Protein Kinase; Protein Kinase C; Proteins; Public Health; Rattus; Receptor, Angiotensin, Type 1; Regulation; Renovascular Hypertension; Risk Factors; Role; Scientist; Sexual Dysfunction; Signal Pathway; Signal Transduction; Signaling Protein; Sodium; Sodium Chloride; Testing; Therapeutic; United States; Vasopressins; Water consumption; Work; blood pressure reduction; blood pressure regulation; citrate carrier; compliance behavior; dosage; extracellular; in vivo; inhibitor/antagonist; insight; kidney cell; novel; novel therapeutics; pressure; receptor; receptor coupling; salt sensitive hypertension; tool; trafficking

DESCRIPTION (provided by applicant): Angiotensin II (Ang II) plays a key role in fluid homeostasis and blood pressure (BP). We have recently found that a seven amino acid peptide (PEP7) encoded within a short open reading frame in exon 2 of the 5' leader sequence of the angiotensin type 1a receptor (AT1aR) mRNA inhibits Ang II activation of extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and regulates AT1aR trafficking in cells. PEP7 also markedly reduced Ang II-mediated sodium intake without having any effect on Ang II-mediated water intake and it antagonized Ang II- induced increases in BP. Aim 1 will determine the signaling mechanism by which PEP7 inhibits Erk1/2 activation. We will test the hypothesis that PEP7 inhibition of Erk1/2 activation is Ang II dependent and mediated via the AT1aR-G protein-independent ß-arrestin signaling pathway. We will also investigate PEP7 regulation of AT1aR vesicular trafficking by inhibiting AT1aR coupling to the ß-arrestin pathway using both pharmacological and molecular approaches, and confocal microscopy. Aim 2 will elucidate the mechanism by which PEP7 regulates fluid and electrolyte homeostasis. We will investigate PEP7 effects in vivo in pathophysiological models of elevated sodium intake including hyponatremic hypovolemia and isotonic hypovolemia as well as conditions that modulate central oxytocin and vasopressin pathways and those that selectively inhibit G protein-mediated protein kinase C and G protein-independent Erk1/2 signaling cascades. Aim 3 will determine if the antihypertensive effects of PEP7 are Ang II-dependent by investigating PEP7 effects on arterial pressure in models of Ang II- and catecholamine- dependent hypertension. We will also determine if PEP7 is effective at lowering BP in two models of salt-sensitivity and what role reduced sodium intake plays in these effects. By achieving these aims, we will gain insight into PEP7 biology that could be leveraged toward developing novel interventions for diseases that are worsened by dietary sodium, like salt- sensitive hypertension.

描述（由申请人提供）：血管紧张素 II (Ang II) 在体液稳态和血压 (BP) 中发挥关键作用。我们最近发现，血管紧张素 1a 型受体 (AT1aR) mRNA 5' 前导序列的外显子 2 的短开放阅读框内编码的七氨基酸肽 (PEP7) 可抑制细胞外信号调节蛋白激酶 1 和 2 (Erk1/2) 的 Ang II 激活，并调节细胞内 AT1aR 的运输。 PEP7 还显着减少了 Ang II 介导的钠摄入量，而对 Ang II 介导的水摄入量没有任何影响，并且它拮抗 Ang II 诱导的血压升高。目标 1 将确定 PEP7 抑制 Erk1/2 激活的信号传导机制。我们将测试以下假设：PEP7 对 Erk1/2 激活的抑制是 Ang II 依赖性的，并通过 AT1aR-G 蛋白独立的 ß-arrestin 信号通路介导。我们还将使用药理学和分子方法以及共聚焦显微镜，通过抑制 AT1aR 与 ß-arrestin 通路的偶联来研究 PEP7 对 AT1aR 囊泡运输的调节。目标 2 将阐明 PEP7 调节体液和电解质稳态的机制。我们将研究 PEP7 在钠摄入量增加的病理生理模型中的体内作用，包括低钠性低血容量和等渗性低血容量，以及调节中枢催产素和加压素途径的条件以及选择性抑制 G 蛋白介导的蛋白激酶 C 和 G 蛋白独立的 Erk1/2 信号级联的条件。目标 3 将通过研究 PEP7 对 Ang II 和儿茶酚胺依赖性高血压模型中动脉压的影响来确定 PEP7 的抗高血压作用是否依赖于 Ang II。我们还将确定 PEP7 在两种盐敏感性模型中是否能有效降低血压，以及减少钠摄入量在这些作用中发挥什么作用。通过实现这些目标，我们将深入了解 PEP7 生物学，可用于开发针对因膳食钠而恶化的疾病（如盐敏感性高血压）的新型干预措施。