About the Lab
The urea cycle functions in the liver to protect the brain from the toxic effects of ammonia, a breakdown product of dietary and cellular proteins. Six urea cycle enzymes and two mitochondrial transporters collectively convert ammonia into urea, which is excreted through the kidneys. Genetic defects in any of the urea cycle enzymes or transporters lead to accumulation of ammonia in the blood — called hyperammonemia — which can irreversibly damage the brain and could be lethal if left untreated. Current treatments for hyperammonemia focus on minimizing accumulation of ammonia through low-protein diet and activation of alternative pathways for ammonia disposal, but none of the treatments focus on protecting the brain from ammonia toxicity. Research in the Caldovic Laboratory focuses on developing new treatments for hyperammonemia and identifying blood biomarkers of brain injury from hyperammonemia.
Ljubica Caldovic, Ph.D. Principal Investigator
Mitochondrial enzymes of the urea cycle cluster at the inner mitochondrial membraneHaskins N, Bhuvanendran S, Anselmi C, Gams A, Kanholm T, Kocher KM, LoTempio J, Krohmaly KI, Sohai D, Stearrett N, Bonner E, Tuchman M, Morizono H, Jaiswal JK and Caldovic L Frontiers in Physiology, accepted for publication (2020)
AMP-activated protein kinase signaling regulated expression of urea cycle enzymes in response to changes in dietary protein intakeHeibel SK, McGuire PJ, Haskins N, Majumdar HD, Rayavarapu S, Nagaraju K, Hathout Y, Brown K, Tuchman M, Caldovic L J Inherit Metab Dis 42(6):1088-1096 (2019)
N-acetylglutamate synthase deficiency due to a recurrent sequence variant in the N-acetylglutamate synthase enhancer regionWilliams M, Burlina A, Rubert L, Polo G, Ruijter GJG, van den Born M, Rüfenacht V, Haskins N, van Zutven LJCM, Tuchman M, Saris JJ, Häberle J, Caldovic L Sci Rep 8(1):15436 (2018)
Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase geneJang YJ, LaBella AL, Feeney TP, Braverman N, Tuchman M, Morizono H, Ah Mew N, Caldovic L Hum Mutat 39(4):527-536 (2018)
A zebrafish model of hyperammonemiaFeldman B, Tuchman M, Caldovic L Mol Genet Metab 113(1-2):142-7 (2014)