Iron is an element essential for virtually all life forms; aberrant iron metabolism is linked to many diseases. These include cancers, neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, iron overload and iron deficiency disorders, iron-loading anaemias, and the anaemia associated with chronic disease. Central to proper iron regulation is the appropriate expression and activity of the liver-expressed regulatory peptide, hepcidin, and the iron exporter, ferroportin (FPN). Modulating the expression and activity of hepcidin and FPN, and their interaction is thus a focus of many therapeutic interventions. We have identified a new mechanism by which ferroportin is regulated. This finding was made possible through the systematic analysis of a cohort of Australian patients with iron overload. Our research proposal builds on this exciting new finding.
Aim 1: To analyse the mechanistic role of these novel proteins in iron homeostasis and FPN regulation.
Aim 2: To investigate the role of these novel proteins in iron homeostasis in animal models of dysregulated iron homeostasis.
Aim 3: To determine the functional consequences of mutations in the se novel proteins and prevalence in subjects with iron overload.
In Aim 1 we will perform functional assays to examine the role of these proteins in FPN function and iron homeostasis. We have unique reagents to be able to study the localisation and function of FPN. We will utilise these reagents to examine the effect of loss or gain of function. The experiments outlined in Aim 2 will determine the molecular role of these proteins in systemic iron homeostasis and in conditions known to affect iron homeostasis. These experiments will also aim at developing an animal model to study the mechanism and effect of loss of these proteins on systemic iron homeostasis to recapitulate the human condition that we see in our patients. In Aim 3 Potential iron overload gene variants will be prioritised and those identified through analysis of the ExAC database, and screened for in other cases of atypical iron overload present in the QIMR Berghofer HH Database.
Approaches, skills and techniques
- Cell culture
- Next generation sequencing
- Flow cytometry
Identification of genes and variants which contribute to iron-related liver disease; their use as diagnostics and potential therapeutics.
Required skills and experience
Candidate interested in learning and utilizing a range of molecular, cellular approaches and novel animal models of disease to understanding iron-related disease. These approaches can be used for virtually all genetic disorders.
Contact the supervisors, Dr Gautam Rishi, Dr Daniel Wallace and Professor Nathan Subramaniam for more information.