|Cell Signalling and Gene Regulation|
|Prof. Proud’s laboratory studies the signalling pathways by which hormones, growth factors and nutrients regulate the function of mammalian cells, especially protein metabolism. The proper control of these pathways plays an important role in cell growth and proliferation, and in neurological processes such as learning and memory. Defects in their control contributes to tumorigenesis, type 2 diabetes, cardiovascular disorders and neurodegenerative disease.|
A major nutrient-sensitive signalling pathway involves the mammalian target of rapamycin, complex 1, mTORC1. mTORC1 is activated by hormones and amino acids, and regulates multiple steps in protein synthesis including the initiation and elongation stages. We are also currently investigating the role of several protein kinases closely related the mTORC1 pathway, all of which directly impact mRNA translation. As direct regulators of key protein synthesis factors, these kinases, which include MNK1, MNK2 and eEF2K, play a central role in cellular metabolism. MNK1 and MNK2 phosphorylate the key translation initiation factor eIF4E.
These projects are available as PhD projects and, modified to suit the time available, as MPhil or Honours projects too.
|Lysosomal Diseases Research Unit (LDRU)|
|The Lysosomal Diseases Research Unit sits within the Nutrition & Metabolism Theme at SAHMRI andis a world research leader in the biochemistry, cell biology and genetics of the lysosome. The Unit’s research has delivered state-of-the-art diagnostics and commercialised first-ever treatments for two lysosomal storage disorders. The lysosomal network is increasingly being implicated in disorders such as stroke, heart disease and neurodegenerative disorders such as Alzheimer’s. The Unit brings its core strength in lysosomal research to investigate the contribution of the lysosomal network in these disorders, with a particular focus on neurodegeneration.|
Honours: Evaluation of a novel drug for the treatment of childhood-onset dementia.
Supervisors: Drs Adeline Lau, Kim Hemsley and Louise O’Keefe
This project examines the therapeutic efficacy of a novel drug for the treatment of Sanfilippo syndrome, a group of five neurological disorders of childhood that is caused by insufficient amounts of one of five lysosomal enzymes, resulting in the cellular accumulation of heparan sulphate. Children experience progressive and profound neurodegeneration and premature death. This project utilisesDrosophila models of two Sanfilippo disorders to examine the capacity of a novel drug to improve disease pathology and neurological function. The student can expect to utilise techniques such as behavioural/neurological testing, mass spectrometry and immunostaining/microscopy. More information: Dr Adeline Lau
|Honours: Characterisation of endocytic machinery of lysosomal storage disorder cells.|
Supervisors: Drs Adeline Lau and Makoto Kamei
Endocytosis is a process by which cells import materials from their surroundings. Impaired endocytosis has been implicated in the neurodegenerative lysosomal storage disorder Sanfilippo type A, a progressive childhood neurological disorder caused by a defect/absence of the lysosomal enzyme, sulphamidase, and accumulation of its substrate, heparan sulphate. This leads to progressively severe clinical problems and premature death in the majority of cases. This project examines and characterises intracellular trafficking mechanisms to identify the pathways that interfere with endocytic vesicular trafficking, and evaluate whether they can be manipulated or normalised to alleviate clinical pathology. The student will utilise fluorescence immunohistochemistry, confocal microscopy, enzyme assays and Western blot analysis. More information : Drs Makoto Kamei or Adeline Lau
|PhD Project: Deubiquitinating enzyme protein complexes involved in endosomal events|
Supervisor: A/Prof Pirjo Apaja [EMBL Australia Group Leader, Organelle Biology and Disease, Lysosomal Diseases Research Unit]
Ubiquitination in the endocytic pathway functions as both a protein interaction as well as degradation signal. The tagging of ubiquitin is performed by specific E3 ubiquitin ligases and removal by deubiquitinating enzymes (DUBs). This dynamic process determines the functional properties of the target proteins. The aim is to characterise DUBs that have a role in the regulation of endosomal signalling and/or cargo trafficking. DUBs are important regulators and are linked to a wide variety of diseases (such as cancers, neurodegenerative, metabolic, and cardiovascular diseases). This project uses CRISPR-Cas9 editing, expression of target DUBs and analysis of cellular locations. Proteomics will be used to identify interacting partners and to study protein-complex dynamics, and for validation of G protein-coupled receptors such as dopamine receptor 4, which is associated with attention deficit hyperactivity disorder. The student can expect to develop skills in protein interaction studies using both biochemical and cell biological assays. Some previous skills in bioinformatics is an advantage.
For more information about this project contact A/Prof Pirjo Apaja
|Honours project: Detection system for cAMP to monitor spatial cellular signalling|
Supervisors: A/Prof Pirjo Apaja [EMBL Australia Group Leader, Organelle Biology and Disease], Dr Makoto Kamei
G protein-coupled receptors (GPCRs) are membrane proteins that are activated by ligands such as neurotransmitters. GPCR activation triggers a cyclic AMP (cAMP)-mediated signalling cascade that results in inhibition or activation of multiple cellular effectors. This project uses fluorescence sensor molecules to detect cAMP in live cells using Fluorescence (Förster) Energy Transfer (FRET). The project involves cloning, expressing and targeting the sensor to specific cellular locations, and analysis of activated signalling using a FRET microscope. The student can expect to develop skills in cell biology, fluorescence microscopy and image-based analyses. The aim is to validate cAMP signalling in different stimulation conditions and the site of activation using wild-type and disease-associated GPCRs (e.g. dopamine receptor 4 is associated with attention deficit hyperactivity disorder).
Ref: Klarenbeek et al. (2015) PlosOne. Apr 14;10(4):e0122513
For more information about the project please contact A/Prof Pirjo Apaja
The Nutrition and Metabolism theme hold regular Research Events:
Students are welcome to attend. The dates for next year's events are below:
For further information please contact - firstname.lastname@example.org