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

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目旨在开发纳米制剂，用于将铜锌超氧化物歧化酶（CuZnSOD）输送到中枢神经系统（CNS），以治疗心血管疾病，如高血压和心力衰竭。血管紧张素II（AngII）循环水平的增加可通过刺激缺乏血脑屏障（BBB）的室周器官（CVO）导致高血压。以前，病毒介导的抗氧化剂基因转移直接注射到CVOs确定超氧化物（O2+-）作为AngII诱导的心血管效应的信号中间体。然而，病毒载体毒性和CNS递送的局限性需要开发替代治疗策略。为此，我们建议将清除细胞内O2+-的CuZnSOD封装到稳定的聚离子复合物“CuZnSOD纳米酶”中。我们假设，外周给药CuZnSOD纳米酶将改善血管紧张素II依赖性神经源性高血压，通过调节血管紧张素能信号在血脑屏障缺陷的CVOs。为了解决这一假设，将测试以下特定目的：1）确定CuZnSOD纳米酶在神经元中的摄取，并研究CuZnSOD纳米酶将功能性CuZnSOD蛋白递送到神经元中的功效; 2）确定CuZnSOD纳米酶的体内生物分布，并测量外周施用后CuZnSOD纳米酶在CVO中的时间表达; 3）确定外周施用CuZnSOD纳米酶对AngII依赖性神经源性高血压的治疗作用。这些研究将为纳米医学驱动的抗氧化疗法治疗CNS相关心血管疾病的效用提供新的见解。

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.