Acute ischemic renal failure is associated with high morbidity and mortality. In renal transplantation ischemia/reperfusion injury is associated with delayed graft function and decreased long-term graft survival. The long-term objective of this program is to use long-acting selective A2A-agonists in reducing renal injury from ischemia/reperfusion in humans. As a step toward this goal, the current proposal describes methods in a rodent model of ischemia/reperfusion injury to develop and test novel long-acting selective A2A-adenosine receptor agonists as compounds to reduce renal tissue injury.
Aim l describes experiments to identify and characterize novel selective long- acting A2A-agonists. We plan to identify the metabolites that accumulate in animals. Specificity will be assessed by radioligand binding and functional assays in human inflammatory cells.
Aim 2 describes experiments to determine the specificity of action of A2A- agonists in vivo and the window of time during which a A2A agonist must be administered in order to produce optimal tissue protection. We will use a well established mouse model of I/R injury. These compounds will be commercialized by a new Biotechnology start-up company, Adenosine Therapeutics, LLC.

Proposed Commercial Applications

We propose to synthesize, characterize and commercialize novel adenosine A2A agonists in order to reduce injury in renal ischemia1reperfusion. Acute renal failure is a common disorder affecting 5% of hospitalized patients and is associated with a mortality of approximately 50%. Based upon our preliminary data, new compounds that we develop for this use, long- acting selective agonists of A2A adenosine receptors, should be potent agents in reducing renal injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
1R41DK058413-01
Application #
6204694
Study Section
Special Emphasis Panel (ZRG1-SSS-G (06))
Program Officer
Wilder, Elizabeth L
Project Start
2000-09-30
Project End
2001-11-30
Budget Start
2000-09-30
Budget End
2001-11-30
Support Year
1
Fiscal Year
2000
Total Cost
$100,000
Indirect Cost
Name
Adenosine Therapeutics, LLC
Department
Type
DUNS #
001016760
City
Charlottesville
State
VA
Country
United States
Zip Code
22902
Awad, Alaa S; Rouse, Michael D; Khutsishvili, Konstantine et al. (2011) Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney Int 79:1090-8
Kinsey, Gilbert R; Okusa, Mark D (2011) Pathogenesis of acute kidney injury: foundation for clinical practice. Am J Kidney Dis 58:291-301
Bajwa, Amandeep; Jo, Sang-Kyung; Ye, Hong et al. (2010) Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury. J Am Soc Nephrol 21:955-65
Kinsey, Gilbert R; Huang, Liping; Vergis, Amy L et al. (2010) Regulatory T cells contribute to the protective effect of ischemic preconditioning in the kidney. Kidney Int 77:771-80
Jo, Sang-Kyung; Bajwa, Amandeep; Ye, Hong et al. (2009) Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury. Kidney Int 75:167-75
Awad, Alaa S; Rouse, Michael; Huang, Liping et al. (2009) Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int 75:689-98
Kinsey, Gilbert R; Sharma, Rahul; Huang, Liping et al. (2009) Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J Am Soc Nephrol 20:1744-53
Okusa, Mark D (2002) A(2A) adenosine receptor: a novel therapeutic target in renal disease. Am J Physiol Renal Physiol 282:F10-8