Molecular and Physiological Analysis of Creatine Transporter Autoregulation

Creatine is an important energy storage and transfer molecule in muscle and brain but is synthesized primarily in the kidneys and liver. Hence, creatine uptake in skeletal muscle, brain, and heart is dependent on the creatine transporter (CrT or SLC6A8). Loss-of-function mutations in CrT are the second most common cause of X-linked intellectual disability and low tissue creatine levels result in skeletal muscle atrophy and are closely associated with heart failure. Cells down-regulate expression of CrT when creatine levels are high, but the mechanisms underlying this autoregulation and the importance to normal physiology and disease are unknown.

Recently, we found that creatine feedback inhibits translation of the CrT mRNA to control transporter production, and we identified elements in the CrT mRNA that are important for this control. This PhD project will involve molecular genetic analyses to more fully characterize the translational control mechanism(s) by which creatine feedback inhibits its own cellular uptake. In addition, CRISPR-Cas technology will be used to eliminate the translational control mechanisms in mice, and then physiological studies of the mice will be used to characterize the role of CrT autoregulation.