Grant: CIHR Fellowship

An enzyme called mTOR (mechanistic target of rapamycin) is a key regulator of cellular growth and survival. mTOR is normally activated or turned on in response to nutrients, but its activity is increased above normal levels in cancer and type 2 diabetes. mTOR is also hyperactivated in mTORopathies, a group of brain disorders characterized by malformations during brain development. Some human mTORopathy patients develop impaired social interactions, so mTORopathies are also considered as Autism Spectrum Disorders (ASDs). A better understanding of how mTOR activation is controlled will provide insight into normal cellular regulation and may reveal ways to treat mTORopathies. Interestingly, mTOR and several proteins that regulate mTOR are localized to or move to specific places in the cell when they are active, but how this is controlled is unclear. To address this question, I probed databases and found that multiple mTOR pathway proteins likely undergo palmitoylation, the addition of a sticky, fatty tag that regulates where in the cell a protein goes. I thus hypothesize that palmitoylation is required for mTOR activation and that blocking palmitoylation will prevent mTOR overactivation in disease states. To test this hypothesis I will first identify the palmitoyl-protein(s) that control mTOR activity and will then determine whether preventing their palmitoylation can reduce disease symptoms in mutant mice that would normally develop mTORopathies. This work will provide new insights into regulation of a pathway that is important for the physiological function of virtually all mammalian cells. Moreover, because 1 in 94 children in Canada currently have an ASD and nearly 2 million people in Canada have been diagnosed with Type 2 diabetes, this work could lead to new treatment strategies for the millions of Canadians who suffer from these diseases.