Novel Peptide Therapeutics for Cardiorenal Protection in Heart Failure

用于心力衰竭心肾保护的新型肽疗法

• 批准号: 9753353
• 负责人: John C Burnett
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753353
• 关键词: ANGPT1 gene; Address; Advanced Development; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animal Model; Apoptosis; Area; Biological; Biological Markers; Cardiac; Cardiac Myocytes; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Congestive; Congestive Heart Failure; Cyclic AMP; Cyclic AMP Receptors; Cyclic GMP; Development; Elements; Engineering; Exhibits; Failure; Fibroblasts; Fibrosis; Foundations; Future; Generations; Goals; Heart failure; Hospitalization; Human; Impaired Renal Function; In Vitro; Inflammation; Kidney; Ligands; Mediating; Mediator of activation protein; Molecular; Myocardial; Natriuretic Peptides; Outcome; Particulate; Pathway interactions; Patients; Peptides; Perfusion; Pharmacology; Physiological; Population; Production; Property; Pump; Renal function; Renin; Renin-Angiotensin-Aldosterone System; Role; Sodium; Structure; System; Testing; Therapeutic; Tubular formation; atrial natriuretic factor receptor A; base; cyclic GMP-binding protein; functional disability; high risk; innovation; kidney cell; novel; novel marker; novel therapeutics; peptide drug; precision medicine; prevent; prognostic; receptor; urinary

PROJECT SUMMARY We advance innovative cardiorenal protective peptide therapeutics for heart failure (HF). Studies will investigate NPA7, a novel, multivalent and first-in-class peptide, engineered by the applicants to co-target two biological pathways. These two targets are the natriuretic peptide/particulate guanylyl cyclase-A receptor/cGMP and Angiotensin1-7/MasR/cAMP systems. We hypothesize that NPA7 mediates cardiorenal protective properties via these complementary pathways and has synergistic actions beyond pGC-A and MasR activation alone. Importantly, we also hypothesize that NPA7 is highly effective in a state of an overactive intrarenal renin-angiotensin-aldosterone system (RAAS) as NPA7 may suppress aldosterone production/release, antagonize AT1, suppress renin and inhibit angiotensinogen (AGT) in the kidney. Preliminary studies in experimental HF reveal that beyond sodium retention and congestion, there is activation of deleterious molecular pathways in the kidney for inflammation, apoptosis, and fibrosis, which may result in progressive worsening renal function and structure with poor outcomes. While multifactorial mechanisms may be involved in progressive renal structural and functional impairment in chronic HF, Angiotensin II (ANG II) is a fundamental mediator. Here NPA7, via pGC-A and MasR, may activate complementary RAAS inhibiting and antagonizing mechanisms with amplified cardiorenal protection. We also advance the concept that urinary AGT (uAGT), which drives the renal generation of ANG II, may serve as a novel pathophysiological biomarker for intrarenal RAAS activation, independent of circulating RAAS. Indeed, a major long-term goal is the development of uAGT as a novel urinary biomarker for intrarenal RAAS to aid in the identification of high-risk HF patients that may benefit from NPA7 therapy. Aim 1: Determine the cardiorenal protective properties of NPA7 in human renal tubular cells, cardiomyocytes and renal and myocardial fibroblasts in vitro. Aim 2: Determine cardiorenal protective and intrarenal RAAS suppressing properties of chronic NPA7 therapy in a large animal model of chronic HF that exhibits myocardial pump failure, reduced renal perfusion with congestion and markedly activated intrarenal RAAS compared to ACEi. Aim 3: Determine uAGT levels in high-risk chronic HF patients and its association with impaired renal function and its predictive power for future HF hospitalization and death.

项目概要 我们推进针对心力衰竭 (HF) 的创新心肾保护肽疗法。研究将 研究 NPA7，这是一种新型多价首创肽，由申请人设计，可共同靶向两种 生物途径。这两个靶标是利尿钠肽/颗粒鸟苷酸环化酶-A 受体/cGMP 和血管紧张素1-7/MasR/cAMP 系统。我们假设 NPA7 介导心肾功能 通过这些互补途径发挥保护作用，并且具有超越 pGC-A 和 仅 MasR 激活。重要的是，我们还假设 NPA7 在 肾内肾素-血管紧张素-醛固酮系统 (RAAS) 过度活跃，因为 NPA7 可能会抑制醛固酮 产生/释放，拮抗 AT1，抑制肾素并抑制肾脏中的血管紧张素原 (AGT)。 实验性心力衰竭的初步研究表明，除了钠潴留和充血之外，还有激活作用 肾脏中炎症、细胞凋亡和纤维化的有害分子途径，这可能会导致 肾功能和结构进行性恶化，结果不佳。虽然多因素机制可能 血管紧张素 II (ANG II) 与慢性心力衰竭的进行性肾结构和功能损害有关，是一种 基本调解者。在此，NPA7 通过 pGC-A 和 MasR 可能激活互补的 RAAS 抑制和 具有增强心肾保护作用的拮抗机制。我们还提出了尿 AGT (uAGT) 驱动 ANG II 的肾脏生成，可能作为一种新的病理生理学生物标志物 用于肾内 RAAS 激活，独立于循环 RAAS。事实上，一个主要的长期目标是 开发 uAGT 作为肾内 RAAS 的新型尿液生物标志物，以帮助识别高风险 可能受益于 NPA7 治疗的心衰患者。目标 1：确定心肾保护特性 体外人肾小管细胞、心肌细胞以及肾和心肌成纤维细胞中的 NPA7。目标 2： 确定长期 NPA7 治疗的心肾保护和肾内 RAAS 抑制特性 慢性心力衰竭的大型动物模型，表现出心肌泵衰竭、肾灌注减少 与 ACEi 相比，充血和肾内 RAAS 显着激活。目标 3：确定 uAGT 水平 高危慢性心力衰竭患者及其与肾功能受损的关系及其对未来的预测能力 心力衰竭住院和死亡。