A NANOZYME ANTIOXIDANT THERAPY FOR THE TREATMENT OF ANGIOTENSIN II-DEPENDANT HYP

用于治疗血管紧张素 II 依赖性 HYP 的纳米酶抗氧化疗法

• 批准号: 8360238
• 负责人: Matthew C. Zimmerman
• 金额: $ 22.31万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360238
• 关键词: Address; Angiotensin II; Antioxidants; Biodistribution; Blood - brain barrier anatomy; Cardiovascular Diseases; Cardiovascular system; Complex; Development; Encapsulated; Funding; Gene Transfer; Grant; Heart failure; Hypertension; Lead; Measures; Mediating; National Center for Research Resources; Nebraska; Neuraxis; Neurons; Organ; Peripheral; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Signal Transduction; Source; Superoxides; Testing; Therapeutic; Therapeutic Effect; Toxic effect; United States National Institutes of Health; Viral; Viral Vector; antioxidant therapy; copper zinc superoxide dismutase; cost; in vivo; insight; nanoformulation; nanomedicine; neurogenic hypertension; polyion; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project seeks to develop nanoformulations for the delivery of copper-zinc superoxide dismutase (CuZnSOD) to the central nervous system (CNS) for treatment of cardiovascular diseases, such as hypertension and heart failure. Increased circulating levels of angiotensin II (AngII) can lead to hypertension by stimulating circumventricular organs (CVOs), which lack a blood-brain-barrier (BBB). Previously, viral-mediated gene transfer of antioxidants injected directly into CVOs identified superoxide (O2+-) as signaling intermediates in AngII-induced cardiovascular effects. However, viral vector toxicities and limitations for CNS delivery require development of an alternative therapeutic strategy. To this end, we propose to encapsulate CuZnSOD, which scavenges intracellular O2+-, into a stable polyion complex, "CuZnSOD nanozyme". We hypothesize that peripherally administered CuZnSOD nanozyme will ameliorate AngII-dependent neurogenic hypertension by modulating angiotensinergic signaling in BBB-deficient CVOs. To address this hypothesis, the following Specific Aims will be tested: 1) Determine the uptake of CuZnSOD nanozyme in neurons and investigate the efficacy of CuZnSOD nanozyme to deliver functional CuZnSOD protein into neurons; 2) Determine the in vivo biodistribution of CuZnSOD nanozyme and measure the temporal expression of CuZnSOD nanozyme in the CVOs following peripheral administration; 3) Determine the therapeutic effect of peripherally administered CuZnSOD nanozyme on the development of AngII-dependent neurogenic hypertension. These studies will provide new insight into the utility of nanomedicine-driven antioxidant therapy for the treatment of CNS-associated cardiovascular diseases.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该项目旨在开发纳米制剂，用于将铜锌超氧化物歧化酶（Cuznsod）递送到中枢神经系统（CNS），以治疗心血管疾病，例如高血压和心脏衰竭。血管紧张素II（ANGII）的循环水平升高会通过刺激缺乏血脑屏障（BBB）的室外器官（CVO）来导致高血压。以前，病毒介导的抗氧化剂的基因转移直接注射到CVO中，鉴定为Angii诱导的心血管效应中的信号中间体的超氧化物（O2+ - ）。但是，病毒载体的毒性和中枢神经系统递送的局限性需要制定替代性治疗策略。为此，我们建议将清除细胞内O2+ - 的Cuznsod封装到稳定的Polyion络合物“ Cuznsod Nanozyme”中。我们假设外周施用的Cuznsod纳米酶将通过调节BBB缺陷型CVO中的血管紧张素信号传导来改善血管依依赖的神经源性高血压。为了解决这一假设，将测试以下特定目的：1）确定神经元中库兹的纳米团的摄取，并研究库兹尼索纳米酶将功能性库兹尼蛋白蛋白传递到神经元中的功效； 2）确定外周施用后CUZNSOD纳米酶的cuznsod纳米酶的体内生物分布，并测量Cuznsod纳米酶的时间表达； 3）确定外周施用的Cuznsod纳米酶对ANGII依赖性神经源性高血压的发展的治疗作用。这些研究将为纳米医学驱动的抗氧化剂治疗对CNS相关的心血管疾病的治疗提供新的见解。