Polyamines (PA) are small cationic molecules required for entry and progression through the cell cycle. To address their increased need for PA, cells with short cycling times up-regulate both PA biosynthesis and PA transport. PA autoregulate when high intracellular PA concentrations induce a full-length active protein, antizyme (Az), via a translational +1 frameshift. Az inhibits both the first and rate-limiting enzyme of PA biosynthesis, ornithine decarboxylase (ODC), and PA transport. This 2 pronged mechanism effectively limits the ability of the cell to acquire PA. The kidney is exceptional in demonstrating high intracellular agmatine (Agm) levels (-400 uM) and high constitutive activity of the enzyme that converts arginine to Agm, arginine decarboxylase (ADC). The kidney appears an important source of systemic Agm. We have recently shown that Agm can induce Az. Agm induction of Az depletes intracellular PA levels in transformed cell lines and markedly inhibits their proliferation. Agm is the only known molecule, exclusive of the canonical PA, with the capacity to induce Az. Further investigation of this kidney derived anti-proliferative molecule is warranted. This proposal demonstrates Agm uptake is via PA transporters. These transporters are undetectable in quiescent cells, and up regulated in rapidly proliferating cells. We hypothesize that Agm selectively targets rapidly proliferating cells. In SA #1 we characterize Agm transport and its dependence on PA transporters. In SA#2 we evaluate targeting via the relative uptake vs. effects of Agm in cell lines representing increasing stages of tumorigenesis. In SA #3 we address the mechanisms of Agm mediated inhibition of proliferation. We hypothesize that this active cell mediated mechanism may be analogous to that noted for senescence. Attaining a K01 award would allow the PI to formally establish his independence for future R01 applications, and to pursue an appointment in the Academic Research series at the University of California San Diego. UCSD has established itself as a leading academic institution and thus provides an excellent environment for the exchange of ideas and techniques essential for the growth of the PI's career.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK002920-03
Application #
6612544
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2001-08-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$126,630
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Declèves, Anne-Emilie; Sharma, Kumar; Satriano, Joseph (2014) Beneficial Effects of AMP-Activated Protein Kinase Agonists in Kidney Ischemia-Reperfusion: Autophagy and Cellular Stress Markers. Nephron Exp Nephrol :
Satriano, Joseph; Sharma, Kumar; Blantz, Roland C et al. (2013) Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease. Am J Physiol Renal Physiol 305:F727-33
Satriano, Joseph; Mansoury, Hadi; Deng, Aihua et al. (2010) Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. Am J Physiol Cell Physiol 299:C374-80
Arndt, Mary Ann; Battaglia, Valentina; Parisi, Eva et al. (2009) The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis. Am J Physiol Cell Physiol 296:C1411-9
Isome, Masato; Lortie, Mark J; Murakami, Yasuko et al. (2007) The antiproliferative effects of agmatine correlate with the rate of cellular proliferation. Am J Physiol Cell Physiol 293:C705-11
Satriano, Joseph; Lortie, Mark J; Ishizuka, Shunji et al. (2006) Inhibition of inducible nitric oxide synthase alters Thy-1 glomeruonephritis in rats. Nephron Physiol 102:p17-26
Satriano, J (2004) Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article. Amino Acids 26:321-9
Satriano, Joseph (2003) Agmatine: at the crossroads of the arginine pathways. Ann N Y Acad Sci 1009:34-43
Deng, Aihua; Munger, Karen A; Valdivielso, Jose M et al. (2003) Increased expression of ornithine decarboxylase in distal tubules of early diabetic rat kidneys: are polyamines paracrine hypertrophic factors? Diabetes 52:1235-9