Evaluation of the Safety and Efficacy of Angiotensin 1-7 to Enhance Cognitive Function in Participants Undergoing Coronary Artery Bypass Graft (CABG) Surgery

评估血管紧张素 1-7 增强接受冠状动脉搭桥术 (CABG) 手术的参与者认知功能的安全性和有效性

• 批准号: 9258891
• 负责人: ANDREW E ARAI
• 金额: $ 74.51万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258891
• 关键词: Address; Advanced Development; Angiotensins; Animals; Anisotropy; Anti-Inflammatory Agents; Anti-inflammatory; Attention; Attenuated; Blood - brain barrier anatomy; Brain; Brain Hypoxia; Brain region; Cardiovascular Diseases; Cells; Cerebrovascular Circulation; Clinical; Clinical Research; Coronary; Coronary Arteriosclerosis; Coronary Artery Bypass; Diffusion; Double-Blind Method; Encephalitis; Endothelial Cells; Evaluation; Goals; Heart Diseases; Human; Impaired cognition; Incidence; Individual; Inflammation; Inflammatory; Interruption; Lateral; Magnetic Resonance Imaging; Measures; Medial; Medical; Memory; Memory Loss; Microglia; National Heart, Lung, and Blood Institute; Neuronal Dysfunction; Neurons; Nitric Oxide; Operative Surgical Procedures; Outcome; Participant; Pathway interactions; Patients; Performance; Perfusion; Peripheral; Placebo Control; Positron-Emission Tomography; Postoperative Period; Production; Quality of life; Randomized; Reactive Oxygen Species; Reporting; Safety; Side; Stroke; Testing; Time; Tissues; Tracer; United States National Institutes of Health; Vascular Endothelial Cell; Vascular Endothelium; Work; angiotensin I (1-7); brain surgery; cerebral microvasculature; cognitive enhancement; cognitive function; cytokine; design; eligible participant; executive function; feeding; follow-up; hospital readmission; insight; language processing; neurovascular unit; novel; novel therapeutics; peptide drug; prevent; primary outcome; processing speed; programs; receptor; repaired; subcutaneous; therapeutic candidate; treatment group; white matter

PROJECT SUMMARY Every year, more than 500,000 patients in the US have coronary artery bypass surgery (CABG) to treat coronary artery disease. However, postoperative outcomes are complicated by a significant incidence of stroke and cognitive impairment. Postoperative cognitive impairment results in decreased quality of life for these individuals and higher hospital readmission rates. There is a clear unmet medical need to find treatments to attenuate or prevent cardiac disease and CABG induced cognitive impairment. Although the precise triggers are debated, CABG increases brain hypoxia and circulating cytokines. Increases in circulating inflammatory cytokines and brain hypoxia result in increased brain reactive oxygen species (ROS) production, activation of brain inflammatory pathways leading to neuronal dysfunction and cognitive impairment. Recent work by our group and others have shown in animals that Angiotensin-(1-7) (Ang-(1-7) can inhibit ROS production, increase nitric oxide production and reduce inflammatory cytokines in the brain, microvasculature and peripheral tissue via activation of the Mas receptor. The ideal therapeutic candidate to treat CABG induced cognitive impairment would be designed to interrupt this cascade by working at both sides of the blood-brain barrier, the brain vascular endothelium and neuronal cells. Ang-(1-7) meets these criteria because Ang-(1-7), acting at the Mas receptor, is known to have anti-inflammatory effects at both endothelial cells and neurons. In Q2 2014, we received regulatory support from the NHLBI SMARTT program to submit an IND to the FDA for the use of Ang-(1-7) to treat cognitive impairment in CABG patients and this IND was approved in August 2015. The present UO1 application is designed to evaluate the safety and efficacy of Ang-(1-7) to enhance cognitive function in participants undergoing CABG surgery. Further, by teaming with the unique capabilities of the NIH Clinical Center, these studies will measure, for the first time, post CABG surgery brain inflammation and microglia activation as measured by PET imaging of [11C]PBR28 and the test the hypothesis that Ang-(1- 7) will result in a decrease in brain inflammation and microglia activation in CABG patients. When completed, this clinical study will have advanced development of a new therapy with potential to treat cognitive impairment in CABG patients.

项目概要 美国每年有超过 500,000 名患者接受冠状动脉搭桥手术 (CABG) 来治疗冠心病 动脉疾病。然而，术后结果因中风和中风的显着发生率而变得复杂。 认知障碍。术后认知障碍会导致这些人的生活质量下降 以及更高的再入院率。寻找减轻或减轻症状的治疗方法显然是一个未得到满足的医疗需求。 预防心脏病和冠状动脉搭桥术引起的认知障碍。尽管确切的触发因素存在争议， CABG 会增加大脑缺氧和循环细胞因子。循环炎症细胞因子增加 大脑缺氧导致大脑活性氧（ROS）产生增加，激活大脑 导致神经元功能障碍和认知障碍的炎症途径。我们组最近的工作 等人在动物身上证明血管紧张素-(1-7) (Ang-(1-7)) 可以抑制 ROS 产生，增加硝酸盐 氧化物产生并减少大脑、微血管和周围组织中的炎症细胞因子 Mas 受体的激活。治疗 CABG 引起的认知障碍的理想治疗候选者 将被设计通过作用于血脑屏障两侧（脑血管）来中断这种级联反应 内皮细胞和神经元细胞。 Ang-(1-7) 满足这些标准，因为 Ang-(1-7) 作用于 Mas 受体， 已知对内皮细胞和神经元具有抗炎作用。 2014年第二季度，我们收到 NHLBI SMARTT 计划的监管支持，向 FDA 提交使用 Ang-(1-7) 的 IND 治疗CABG患者的认知障碍，该IND于2015年8月获得批准。目前的UO1 该应用程序旨在评估 Ang-(1-7) 增强认知功能的安全性和有效性 接受冠状动脉搭桥手术的参与者。此外，通过与 NIH 临床的独特能力合作 中心，这些研究将首次测量 CABG 手术后的脑部炎症和 通过 [11C]PBR28 的 PET 成像测量小胶质细胞活化，并检验 Ang-(1- 7) 将导致 CABG 患者的脑部炎症和小胶质细胞活化减少。什么时候 完成后，这项临床研究将进一步开发一种有潜力治疗认知障碍的新疗法 CABG 患者的损伤。