Research

Nutrient sensing and signalling:- the role of transporter proteins

Research in my laboratory (currently funded by BBSRC) centres on the mechanisms of amino acid (including thyroid hormone) transport across mammalian cell membranes, their regulation by various factors and their physiological functions in health and disease. We make extensive use of Xenopus oocytes as a cellular expression system with which to study cell function (see Figure 1). A major long-term goal is to establish the principal mechanism(s) by which vertebrate cells sense and signal "availability" of amino acids to the cell interior. We are focusing on (i) involvement of amino acid transporters such as the SNATs in regulating / effecting the sensing step, (ii) the linking of sensor mechanisms to the mTOR signalling pathway and (iii) sensing related to the osmotic effects of amino acids on cell volume. We are currently involved in elucidating the molecular mechanisms and physiological regulation of SNAT2 (System A) and LAT1 (System L) amino acid transporters. Pathophysiological modulation of the activity of these transporters in tissues such as liver and skeletal muscle may be a key factor in early development of many catabolic (i.e. lean-tissue wasting) disorders. The knowledge we gain is therefore likely to have therapeutic application in improving whole-body nitrogen balance in catabolic states.

My other research focus is on thyroid hormone (TH) binding and translocation at the cell surface in relation to both genomic and nongenomic TH actions. We are examining the role of membrane transport in TH signalling in mammalian tissues (including liver, thyroid, adipose and placenta) during normal and altered thyroid status. This follows our discovery that a major mechanism of TH transport is via the System L amino acid transporter. The overall aim is to identify specific TH transporters in cell membranes as potential molecular targets for therapy of TH disorders. We are also investigating the possibility that TH exert some key nongenomic actions after they become metabolised to iodothyronamines in peripheral tissues.