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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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)，用于治疗高血压和心力衰竭等心血管疾病。循环中血管紧张素II(AngII)水平的升高可通过刺激缺乏血脑屏障(BBB)的脑室周围器官(CVO)而导致高血压。以前，病毒介导的抗氧化剂基因转移直接注射到CVO中，发现超氧化物(O2-)是血管紧张素转换酶诱导的心血管效应的信号中间产物。然而，病毒载体对中枢神经系统的毒性和局限性要求开发替代的治疗策略。为此，我们建议将清除细胞内O2-的CuZnSOD包裹在一个稳定的多离子络合物中，即CuZnSOD纳米酶。我们推测，外周应用CuZnSOD纳米酶将通过调节BBB缺陷的CVO中的血管紧张素能信号来改善Angii依赖性神经源性高血压。为了解决这一假说，我们将测试下列特定目标：1)测定CuZnSOD纳米酶在神经元中的摄取，并研究CuZnSOD纳米酶将功能性CuZnSOD蛋白输送到神经元的有效性；2)测定CuZnSOD纳米酶在外周给药后在CVO中的体内生物分布和测定其在体内的表达；3)确定外周给药对血管紧张素依赖型神经原性高血压的治疗效果。这些研究将为纳米药物驱动的抗氧化疗法在治疗中枢神经系统相关心血管疾病方面的应用提供新的见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.