*EASTBIO* Defining novel transport mechanisms for volume-regulating corticosteroids in the collecting duct of the kidney.

Corticosteroids are critical volume-regulating hormones which target the collecting duct of the kidney where they rapidly alter Na+ and H2O transport, a process which underpins the “fine-tuning” of total body Na+ balance and maintains our circulating volume. Under physiological conditions the mineralocorticoid aldosterone acts specifically in the collecting duct due to the activity of the enzyme 11bHSD2 which converts the much more abundant glucocorticoid cortisol to an inactive metabolite. However, under certain conditions, glucocorticoids may also stimulate Na+ transport. Much is known about the steroid receptors that these hormones bind, subsequent transcriptional events and their effects upon ion transport. Little, however, is known regarding the movement of these hormones beyond their lipophilic nature, endowing them the ability to diffuse freely across plasma membranes.

Recently in our lab, we have generated transcriptomic profiles mapping the genetic signals underpinning corticosteroid-induced Na+ transport in a cellular model of the collecting duct. We have identified several families of membrane transporters whose expression are regulated by acute treatment with corticosteroids. Preliminary studies revealed that corticosteroids may in fact be actively transported in a directed manner, with asymmetrical distribution of hormones on either side of the monolayer and negligible intracellular concentrations. Whilst little has been described in the field regarding active corticosteroid transport specifically in the collecting duct, other groups have shown that corticosteroids can be actively transported elsewhere in the body e.g. brain and adipose tissue.

The aim of this project is to define and characterise these novel transport mechanisms and identify the endogenous transporters involved. The student will gain experience in a range of cutting-edge techniques:
• Isolation and culture of primary murine collecting duct epithelia
• Quantification of corticosteroids using mass spectrometry
• Fluorescence microscopy to localise transporters in cells and tissue
• CRISPR-Cas9 gene editing to delete putative transporters in collecting duct cells
• Electrophysiological measurements of transepithelial ion transport

The successful candidate will be based at the heart of St Andrews Science campus at North Haugh as part of the Biomedical Sciences Research Complex, an interdisciplinary centre bringing together biology, chemistry, physics and medicine. The primary supervisor Dr. Mansley is an epithelial physiologist with expertise in hormone-regulated epithelial ion transport based at the University of St Andrews and the second supervisor Dr. Homer is an analytical chemist with expertise in quantitative steroid analysis based at The University of Edinburgh. Students will attend departmental seminars, regularly present their research at lab and inter-departmental meetings and will also attend and present at external scientific meetings.

How to apply

Applications are welcome from enthusiastic students who hold a first or upper second class Honours degree (or equivalent) in Physiology, Molecular or Cellular Biology, Analytical Chemistry or related area / subject. As an equal opportunities institution, we welcome applicants regardless of gender, ethnicity, disability, sexual orientation and transgender status - all appointments are made on merit.
Please direct any informal enquiries to Dr. Morag K. Mansley ([Email Address Removed]).

More information about the lab group and supervisors can be found at https://bit.ly/3jKaYr9 and https://bit.ly/2SF00Hv.

Applicants should submit the EASTBIO application to [Email Address Removed]. To receive an application form, please email [Email Address Removed] or use the link http://www.eastscotbiodtp.ac.uk/how-apply-0