Growth factor signaling dramatically changes cellular behavior, and requires commensurate
alterations in cellular metabolism. Disturbed growth factor signaling is a well-known mechanism underlying heritable diseases of the connective tissue - the tissue that provides structural support and a medium for cellular communication - that present with structural anomalies of the cardiovascular system. Among those, the arterial tortuosity syndrome (ATS) is a prime example characterized by tortuosity, narrowing and widening of the arteries.
We previously showed that mutations in SLC2A10, encoding the glucose transporter GLUT10,
cause ATS. GLUT10 most likely mediates transport of dehydroascorbic acid (DHA) into the
mitochondria where it is converted to ascorbic acid. In a zebrafish model for ATS, we found
disturbed growth factor signaling and abnormal functioning of the mitochondria -the energy
fabrics of the cell - in an early stage of development. This project will analyze the exact
mechanisms by which GLUT10 deficiency connects to reduced mitochondrial functioning and
altered growth factor signaling. We will study 2 animal models. The early stage will be analyzed in a zebrafish model, while late stages and the natural history of the disorder will be studied in a mouse model made incapable of synthesizing ascorbic acid. This project aims at a better understanding of the development and maintenance of the cardiovascular system through study of the biological mechanisms in ATS.