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Dissecting the mechanisms of mTOR activation. Supervisor: Dr. Zita Balklava Collaboration with Dr. Thomas Wassmer (Aston University) Background: Alzheimer's disease is the most common form of dementia in old age. Amyloid Precursor Protein (APP) plays a key role in Alzheimer's disease (AD). Mutations in APP gene cause an early onset or familial form of AD. The aberrant processing of APP by secretases is thought to be a key driver in AD as familial forms of AD are also caused by mutations in gamma secretase. Despite its significance in AD the physiological role of APP still remains illdefined. APP is a transmembrane receptor and has been suggested to regulate cell signalling, but the pathways it controls and mechanisms involved remain elusive. In our previous studies we have shown that APP directly binds the mechanistic target of rapamycin (mTOR), a key signalling hub that that regulates numerous cellular and developmental processes. Using C.elegans as a model system we have demonstrated that C.elegans homologue of APP (APL-1) controls numerous mTOR dependent processes such as germline expansion, fat metabolism and autophagy. By RNA-mediated interference approach we have also demonstrated that APL-1 regulates mTOR activity by mediating input of amino acids through RAG-GTPases. Project: Powerful genetics of C.elegans has been proven to be beneficial in studying cell signalling pathways in vivo, and therefore will be used in this project. Broad aim of this project is to decipher the mechanism of how APP controls mTOR activation by RAG-GTPases using C.elegans germline expansion as a model assay. This will include cloning expression constructs for RAG-GTPases in their native, constitutively active and inactive states and introducing them into C.elegans to create transgenic strains. These will then be crossed into control and APL-1 mutant strains in combination with overexpression of APL-1. Resulting mutant transgenic strains will be used for epistasis analysis to gain insights into mechanisms of mTOR activation.