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: 7960470
• 负责人: Matthew C. Zimmerman
• 金额: $ 22.16万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960470
• 关键词: Address; Angiotensin II; Antioxidants; Biodistribution; Blood - brain barrier anatomy; Cardiovascular Diseases; Cardiovascular system; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Encapsulated; Funding; Gene Transfer; Grant; Heart failure; Hypertension; Institution; Lead; Measures; Mediating; Nebraska; Neuraxis; Neurons; Organ; Peripheral; Proteins; Research; Research Personnel; 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; 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. 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.

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