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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR021937-04
Application #
8360238
Study Section
Special Emphasis Panel (ZRR1-RI-2 (01))
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$223,081
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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