An increased endogenous synthesis of oxalate is the underlying cause of the rare genetic disease, primary hyperoxaluria. This disease can be fatal due to renal failure and oxalate deposition in tissues, particularly if it manifests during infancy. Endogenous oxalate synthesis may also play a role in idiopathic calcium oxalate nephrolithiasis and decreasing the amount synthesized could be an effective therapeutic strategy. Despite the clinical significance of endogenous oxalate synthesis, the biosynthetic pathways that lead to its synthesis are largely unknown. The long-term goals of this research project are to define the pathways involved in oxalate synthesis and to develop therapies that will effectively reduce it.
The specific aims of this proposal have been developed to determine which sugars and amino acids contribute to oxalate synthesis, to identify the metabolic pathways involved, and to gain an insight into the regulation of these synthetic pathways. Our research will utilize a recently developed technique, ion chromatography coupled with mass detection (IC/MS), to pursue these specific aims. This technique will allow the use of stable isotopes of sugars and amino acids to determine whether their catabolism leads to oxalate synthesis. Experiments will be conducted in cultured cells and in human subjects infused with isotopes to examine this catabolism. Culture media, blood and urine will be assayed by IC/MS and other procedures. The effects of hormones, principally glucagon, on these catabolic pathways will be examined to elucidate their regulation. These experiments will increase our understanding of the steps involved in endogenous oxalate synthesis and may lead to better therapies to treat individuals with the primary hyperoxalurias and with calcium oxalate stone disease. Primary hyperoxaluria is a rare genetic disease that can significantly alter the health of affected individuals and cause a life-long concern for them and their families. Understanding the reactions that occur in the body to cause this disease could lead to the design of better treatments, not only for individuals with this disease, but possibly for those who suffer from the much more prevalent calcium oxalate stone disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073732-04
Application #
7574376
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rasooly, Rebekah S
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2009
Total Cost
$279,931
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Surgery
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Wood, Kyle D; Holmes, Ross P; Knight, John (2016) RNA interference in the treatment of renal stone disease: Current status and future potentials. Int J Surg 36:713-716
Holmes, Ross P; Knight, John; Assimos, Dean G (2016) Lowering urinary oxalate excretion to decrease calcium oxalate stone disease. Urolithiasis 44:27-32
Knight, John; Madduma-Liyanage, Kumudu; Mobley, James A et al. (2016) Ascorbic acid intake and oxalate synthesis. Urolithiasis 44:289-97
Knight, John; Wood, Kyle D; Lange, Jessica N et al. (2016) Oxalate Formation From Glyoxal in Erythrocytes. Urology 88:226.e11-5
Summitt, Candice B; Johnson, Lynnette C; Jönsson, Thomas J et al. (2015) Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria. Biochem J 466:273-81
Lange, Jessica N; Mufarrij, Patrick W; Easter, Linda et al. (2014) Fish oil supplementation and urinary oxalate excretion in normal subjects on a low-oxalate diet. Urology 84:779-81
Knight, John; Hinsdale, Mark; Holmes, Ross (2012) Glycolate and 2-phosphoglycolate content of tissues measured by ion chromatography coupled to mass spectrometry. Anal Biochem 421:121-4
Lange, Jessica N; Wood, Kyle D; Knight, John et al. (2012) Glyoxal formation and its role in endogenous oxalate synthesis. Adv Urol 2012:819202
Riedel, Travis J; Knight, John; Murray, Michael S et al. (2012) 4-Hydroxy-2-oxoglutarate aldolase inactivity in primary hyperoxaluria type 3 and glyoxylate reductase inhibition. Biochim Biophys Acta 1822:1544-52
Knight, John; Assimos, Dean G; Callahan, Michael F et al. (2011) Metabolism of primed, constant infusions of [1,2-¹³C?] glycine and [1-¹³C?] phenylalanine to urinary oxalate. Metabolism 60:950-6

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