Iron is an essential nutrient at any stage of life, however, it is particularly important for the rapid growth and development that occurs soon after birth. In young infants, intestinal iron absorption is extremely efficient, but following weaning, it declines dramatically to adult levels. Our studies to date have suggested that iron absorption during suckling is dependent on the iron transport protein ferroportin (Fpn), as it is in adults, but systemic signals that are able to reduce absorption post-weaning are ineffective in neonates. This provides a novel strategy for maximizing iron intake at a time of high demand, while retaining the capacity to regulate internal iron trafficking and respond to various insults, such as infection. In this project the mechanisms underlying this hypo-responsiveness will be investigated.
To investigate the mechanism by which intestinal Fpn does not respond to systemic signals in early postnatal life and to determine how the iron homeostasis of neonates responds to infection and inflammation.
Most of the studies to be carried out will use the mouse as a model, but some of the work will utilize intestinal biopsies from human infants. Initial studies will assess in detail the response of the intestine and spleen (as the internal organ that shows the highest level of Fpn-dependent iron release) to systemic inflammatory signals and infection with Pseudomonas aeruginosa. This work will be carried out in mice before and after weaning. The distribution and expression of Fpn will be studied, as will iron trafficking into and around the body. Fpn will be isolated from pre- and post-weaning gut and analysed by contemporary proteomic methods to detect post-translational modifications. The effects of any modifications will be examined in cells transfected with either wild-type Fpn or Fpn in which the modified residues have been mutated. We will also examine human infant intestinal biopsies for these modifications. Understanding the factors responsible for the high absorption in neonates provides the potential for modifying absorption pharmacologically.
Techniques to be used include mouse breeding and phenotypic analysis, in vivo iron kinetic analysis, microscopy, immunohistochemistry, proteomic analysis, protein-protein interaction studies, cell transfection and protein expression.
- This project can be modified to suit Honours, PhD or Clinical students.