Glafira Ermakova MSc Candidate Chin-Sang Lab Investigating the effect of tumour suppressor PTEN/DAF-18 variants and mammalian insulin on the insulin and insulin-like signaling pathway in Caenorhabditis elegans The insulin and insulin-like growth factor signaling (IIS) pathway is highly conserved across all metazoans and is responsible for a variety of developmental processes in which disruptions can lead to dysregulated cell growth. The IIS pathway gets activated in the presence of high levels of nutrients and its primary role is to cause a growth-stimulating response throughout the organism. Due to the pathway’s anabolic nature, it’s overactivation may cause excessive cell proliferation, tumour formation, and even behavioural impairments such as autism spectrum disorder (ASD). As any other key pathway, proteins play an important role up and downregulating the overall effects of the IIS pathway. In humans, tumour suppressor protein Phosphatase and Tensin Homolog, also known as PTEN inhibits IIS, preventing excessive growth and development. The IIS pathway is highly conserved between mammals and the model organism Caenorhabditis elegans (C. elegans). However, while insulin acts as an activator of the IIS pathway in mammals, in C. elegans mammalian insulin has been shown to act as an antagonist, further complicating the role of insulin in C. elegans. The first aim of my thesis research was to work with C. elegans to characterize variants of the human tumour suppressor PTEN in worms by looking at effect of 5 mutations in the homologous C. elegans protein DAF-18. By determining the effects of these mutations on the model organism C. elegans, we can potentially infer how these variants play a role in human disease formation, such as the development of ASD. The second aim of my research was to explore the effect of mammalian insulin on the development of C. elegans. A potential treatment for diseases involving hyperactivation of the IIS pathway might involve an engineered antagonistic human insulin which could bind to the insulin receptor and downregulate it through competitive inhibition. However, if C. elegans is to be used as a model to study human insulin and its activation properties on the IIS pathway, we first need to elucidate the effect of the human insulin on the C. elegans insulin receptor DAF-2. If human insulin can have an agonistic effect on our model organism, then we might be able to use it as an assay to assess the function of human insulin in vivo.
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