Hyperammonemia caused either by inborn errors of metabolism, liver failure or extreme catabolic stress can be life threatening and can cause severe brain damage resulting in intellectual and developmental disabilities. Available therapies are mainly targeted at reducing blood ammonia levels and although they can fervent death from brain edema, they are inefficient at reducing or preventing brain damage. Here we propose to develop novel treatment aimed at protecting the brain from elevated levels of blood ammonia. The proposed studies will use zebrafish and mouse models of hyperammonemia to screen and validate small molecules for their ability to provide neuroprotection from hyperammonemia. In addition, biomarkers for hyperammonemia will be explored in zebrafish to gain insights into the mechanisms of neuroprotection afforded by selected small molecules.
The specific aims are: 1. To identify small molecules that afford protection from ammonia using a 2- stage screen in zebrafish and NAGSko mice.
This aim will be accomplished by high throughput screening of small molecule libraries in zebrafish exposed to hyperammonemia followed by validation of effective molecules in a mouse genetic model of hyperammonemia (NAGSko). 2. To establish biochemical and molecular biomarkers of hyperammonemia in zebrafish.
This aim will use biochemical and gene expression methods in zebrafish to gain insights into the mechanisms of hyperammonemia and how protective molecule exert their effects on the brain in the context of these mechanisms. Overall, this exploratory project takes a new direction in tackling the devastating effects of hyperammonemia. If successful, drugs that result from this projects would be complementary to current treatment approaches eventually improving the outcome of patients with hyperammonemia.

Public Health Relevance

This project is dedicated to the screen for drugs that will protect the brain from the toxic effects of ammonia and thus reduce and eventually eliminate brain damage from hyperammonemia. We will use zebrafish to quickly screen small molecule libraries for compounds that can protect zebrafish from ammonia toxicity;compounds that protect zebrafish from ammonia toxicity will then be tested in the mouse model of NAGS deficiency. The results from this project could lead the development of new treatments to protect the brain from the toxic effects of ammonia.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Leschek, Ellen W
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Children's Research Institute
United States
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Feldman, B; Tuchman, M; Caldovic, L (2014) A zebrafish model of hyperammonemia. Mol Genet Metab 113:142-7