SP 1 - PeriNAA
Data-driven mechanistic modelling of N-acetylaspartate metabolism
Canavan disease (CD) is a leukodystrophy that is caused by deficiency of the enzyme aspartoacylase which leads to an accumulation of N-acetylaspartate (NAA) in the brain. CD coincides with severe neurodegeneration and short life expectancy. Despite the causitive mutations being known, the exact disease mechanism is still not understood. No cure for CD is available and treatment options are limited to palliative care. There is increasing evidence, that NAA metabolism also plays an important role in other tissues and cell types such as adipose tissue, immune cells, as well as lung and cancer cell lines. However, the role of NAA in peripheral tissues and the impact of elevated NAA levels in CD patients on processes outside the brain is completely unclear.
To obtain a mechanistic understanding of NAA in cellular metabolism and signalling processes, we will develop a computational model of these processes. This dynamical model will be based on ordinary differential equations and will be calibrated based on mass spectrometry, sequencing and other data generated by our partners. Using this model, we will generate hypotheses regarding the role of NAA in metabolism and signalling which will be validated by experimental partners. Thereby we will iteratively improve our understanding of the role of NAA. Later on, we want to derive patient-specific models to understand potential differences in the disease pattern of individual CD patients.