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Metabolic drivers of cellular damage in low oxygen

Carlsbergfondets internationaliseringsstipendier

What

All animals die when deprived of oxygen, but some animals, such as the African naked-mole rat, can survive oxygen deprivation much longer than others. Without oxygen, metabolism is reprogrammed, which leads to several negative consequences such as energy deprivation, acidosis and oxidative damage when oxygen returns.

This project will investigate how the naked-mole rat is able to avoid these negative consequences to survive prolonged oxygen deprivation. Specifically, we will focus on the metabolic reprogramming during oxygen deprivation in the naked-mole rat heart and whether they have evolved specific biochemical tricks to survive oxygen deprivation.

Why

Although oxygen is essential for life, the consequences of hypoxia for cells and organisms are not well understood from a biological perspective, but have been studied more intensively in recent years in pathological settings in medical research, including heart infarction, stroke, diabetes and cancer.

My intention is to exploit the knowledge and methodological approaches from the biomedical research to determine the molecular basis for how animals differ in their tolerance to varying oxygen levels.

How

To investigate how naked-mole rats regulate metabolism I will expose isolated hearts and whole animals to oxygen deprivation and measure how metabolic intermediate levels change using mass-spectrometric metabolomics. This will be coupled with mass-spectrometric proteomics and enzyme kinetics measurements to establish whether the activity of metabolic enzymes are modified post-translationally during oxygen deprivation.

Together this will give a detailed overview of metabolic regulation in an extraordinarily hypoxia tolerant mammal.

SSR

Studying basic energy metabolism in response to oxygen deprivation is relevant to several diseases including stroke, cancer and diabetes, and so will reveal novel drug targets to treat these diseases, as is already exploited by the biomedical industry.