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. We propose to synthesize, characterize, and test several new metal (Cu and Zn) complexes of salicylic acid and aminothiol derivatives as catalytic antioxidants that scavenge a wide range of reactive oxygen species (ROS), such as superoxide dismutase (SOD), hydrogen peroxide, peroxynitrite, and lipid peroxyl radicals. Several compounds in this class have been shown to be efficacious in a variety of ways in in vitro and in vivo oxidative stress models of human diseases. Our preliminary data strongly indicate that these metal complexes satisfy many of the criteria for prevention and treatment of cisplatin-induced nephrotoxicity, as they are active, stable, and nontoxic antioxidants. Thus, we hypothesize that Cu- and Zn-metallo-element chelates will protect kidney tubular epithelial cells from cisplatin injury because these chelates have antioxidant activity, and can suppress apoptosis and facilitate recovery. We propose two specific aims:
Aim 1 : Synthesize and characterize the Cu- and Zn-metalloelement chelates.
This aim will focus on chemical studies of new and previously known but not fully characterized compounds.
And Aim 2 : Test the nephroprotective activity of the metallocompounds in biological systems. The study will involve (1) an assessment of antiapoptotic activity of the SOD-mimetic metal chelates with regard to cellular mechanisms by which metal chelates may prevent cisplatin-induced proximal tubule cell death;(2) an examination of the mechanism by which metal chelates suppress apoptosis by preventing cisplatin-induced translocation of proapoptotic Bax from the cytosol to the mitochondria;(3) a study of how metal chelates prevent cisplatin-induced cytochrome c release from the inner mitochondrial membrane and its appearance in the cytosol, and significantly reduces cisplatin-induced caspase-3 activation, based on the SOD-mimetic, catalase-mimetic, and/or peroxidase-mimetic reactivities of metal chelate enzymes required to overcome cisplatin-induced pathology;and (4) a determination of the effects of metal chelates on endonuclease G leakage from mitochondria, its nuclear import, and apoptotic DNA fragmentation. A logical extension of the studies in this proposal carried out in vitro will be extended in vivo. More specifically, we plan to study the mechanisms by which the SOD-mimetic and metal chelates offer protection to cisplatin-induced biological system. For these studies, we will collaborate with investigators at UAMS who have a long-standing interest and enthusiasm in studying metal chelates and mimetic activities of essential metal chelates.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
2P20RR016460-09
Application #
8168101
Study Section
Special Emphasis Panel (ZRR1-RI-7 (01))
Project Start
2010-05-19
Project End
2011-04-30
Budget Start
2010-05-19
Budget End
2011-04-30
Support Year
9
Fiscal Year
2010
Total Cost
$122,147
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Caviness, Perry; Bauer, Ryan; Tanaka, Keisuke et al. (2018) Ca2+ -induced orientation of tandem collagen binding domains from clostridial collagenase ColG permits two opposing functions of collagen fibril formation and retardation. FEBS J 285:3254-3269
Doyle, Erin L; Fillman, Christy L; Reyna, Nathan S et al. (2018) Genome Sequences of Four Cluster P Mycobacteriophages. Genome Announc 6:
McSweeney, Jean C; Hudson, Teresa J; Prince, Latrina et al. (2018) Impact of the INBRE summer student mentored research program on undergraduate students in Arkansas. Adv Physiol Educ 42:123-129
Wolyniak, Michael J; Reyna, Nathan S; Plymale, Ruth et al. (2018) Mass Spectrometry as a Tool to Enhance ""-omics"" Education. J Microbiol Biol Educ 19:
Musa, Aliyu; Ghoraie, Laleh Soltan; Zhang, Shu-Dong et al. (2018) A review of connectivity map and computational approaches in pharmacogenomics. Brief Bioinform 19:506-523
Hill, Brent J F; Dalton, Robin J; Joseph, Biny K et al. (2017) 17?-estradiol reduces Cav 1.2 channel abundance and attenuates Ca2+ -dependent contractions in coronary arteries. Pharmacol Res Perspect 5:
Allison, Devin; Delancey, Evan; Ramey, Hunter et al. (2017) Synthesis and antimicrobial studies of novel derivatives of 4-(4-formyl-3-phenyl-1H-pyrazol-1-yl)benzoic acid as potent anti-Acinetobacter baumannii agents. Bioorg Med Chem Lett 27:387-392
MacNicol, Melanie C; Cragle, Chad E; McDaniel, F Kennedy et al. (2017) Evasion of regulatory phosphorylation by an alternatively spliced isoform of Musashi2. Sci Rep 7:11503
Gao, Bo; Li, Guojun; Liu, Juntao et al. (2017) Identification of driver modules in pan-cancer via coordinating coverage and exclusivity. Oncotarget 8:36115-36126
Rahmatallah, Yasir; Zybailov, Boris; Emmert-Streib, Frank et al. (2017) GSAR: Bioconductor package for Gene Set analysis in R. BMC Bioinformatics 18:61

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