BSc (Hons), DPhil
Postdoctoral Research Fellow
My research focuses upon the roles of acidic (endo-lysosomal) organelles in Ca2+ signaling. Elevating the intracellular [Ca2+] is a ubiquitous signal transduction mechanism, and there has been a recent explosion of interest in endo-lysosomes as unique Ca2+ stores with unique Ca2+ channels activated by a unique second messenger, NAADP.
The main thread running through my work has been the role of acidic organelles in generating (and responding to) complex Ca2+ signals. In particular:
- Two-pore channels (TPCs) are indispensable for NAADP Ca2+ signaling.
- Exocytotic vesicles are signaling hubs that generate their own Ca2+ signals in an autocrine manner.
I recently conducted my Todd-Bird Junior Research Fellowship (New College, Oxford), in the department, working with Antony Galione and Fran Platt, world-leaders in endo-lysosomal Ca2+ signaling and lysosomal storage disorders, respectively. These two fields are rapidly converging with a substantial overlap of interest and these two groups have an ongoing, lively collaboration.
My work dissects the elegant customization of acidic organelles in generating Ca²⁺ signals in immune cells, using techniques appropriate to studying endo-lysosome function: molecular biology, protein biochemistry, and fluorescence microscopy (epifluorescence, 4D confocal).
Aberrant Ca2+ signaling underlies the cause (or progression) of sundry diseases including immune deficiency and therefore the interrelationship between disease and basic biology means that one informs the other. To this end our working hypotheses are:
- Acidic organelles are unique autonomous “signalsomes” that possess all the elements required to generate and respond to Ca²⁺ signals.
- Acidic organelles are crucial for normal immune cell function and their dysregulation leads to disease phenotypes.
Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.
Fineran P. et al, (2016), Wellcome Open Res, 1
Expression of Ca²⁺-permeable two-pore channels rescues NAADP signalling in TPC-deficient cells.
Ruas M. et al, (2015), EMBO J, 34, 1743 - 1758
TPC: the NAADP discovery channel?
Morgan AJ. et al, (2015), Biochem Soc Trans, 43, 384 - 389
Preferential Coupling of the NAADP Pathway to Exocytosis in T-Cells.
Davis LC. et al, (2015), Messenger (Los Angel), 4, 53 - 66
Imaging approaches to measuring lysosomal calcium.
Morgan AJ. et al, (2015), Methods Cell Biol, 126, 159 - 195