Dr Lynn McKeown
2000 - 2004 PhD “Investigation of Integrin Dynamics in Migrating Cells”
Wellcome Trust Centre for Cell-Matrix Research, University of Manchester
1996 – 2000 BSc (Hons) 2:1, Biomedical Sciences with 1 year Industrial Placement, University of Manchester
2015 – University Academic Fellow in cardiovascular biology, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds
My research focusses on molecular mechanisms that regulate the function of the blood vessels specifically how Ca2+ signalling events relate to vascular physiology and disease in endothelial cells. My ultimate aim is to find drugs that will contribute to cardiovascular health by targeting specific molecular interactions that underlie cardiovascular disease.
2014 – 2015 Senior Research Fellow, LICAMM, School of Medicine, University of Leeds
BHF project grant (Feb. 2014).
2013 – 2014 Research Fellow, Food Science, University of Leeds
2008 – 2013 Research Fellow, Faculty of Biological Sciences, University of Leeds
2004 – 2008 Research Associate, Channel and Transporters, University of Manchester
- MRC Project Grant. MR/T004134/1. £237,000. (PI). Dec 2019 – Nov 2021. The role of Rab46 in inflammatory-mediated diseases.
- 4 yr BHF Non-Clinical PhD Studentship. £170,000. (PI) Sept 2018 – Sept 2022. The role of shear stress in Weibel-Palade body function in endothelial cells.
- 4 yr BHF Non-Clinical PhD Studentship. £170,000. (Co-I). Sept 2018 – Sept 2022. In-situ dynamic structure of Rab46 – a novel endothelial protein.
- 3 yr BHF Non-Clinical PhD Studentship FS/17/43/33003. £104,000. (PI). Sept 2017 – Sept 2020. Role of Ca2+ signalling in Weibel-Palade body trafficking.
- University of Leeds Anniversary PhD Studentship. ~ £40,000. (PI). Sept 2016 – Sept 2019. The function of Rab46 in vascular endothelial cells.
- MRC NIRG. MR/N000285/1. £517,000. (PI). Sept 2015 – March 2019. Mechanisms and functions of CRACR2A-L Rab GTPase in vascular endothelial cells.
- BHF Project Grant. PG/13/52/30346. £140,000. (PI). Feb 2014 – Sept 2015, £140000. The role of Tunneling NanoTubes in endothelial cells
- Principal Investigator
- Lecturer in School of Medicine
My ultimate research vision is to reveal fundamental processes required for stimulus-coupled cell secretion with the ultimate aim of identifying novel therapeutic targets for the treatment of cardiovascular disease (CVD). Despite advances in treatment, CVD remains the number one cause of death in the UK. It is evident that endothelial cells, the cells that line all the blood vessels in the body, play a major role in the development of atherosclerosis, a key determinant of CVD. An important aspect of these cells is their ability to store pre-made pro-inflammatory and pro-immunogenic factors, which are then released to enable healthy vascular homeostasis and repair. My hypothesis is that the regulatory mechanisms underlying endothelial cell secretion are disturbed in early CVD and contribute to disease progression. My vision is to transform understanding of endothelial cell release mechanisms and use this information to develop novel targets for therapeutic strategies.
My overall strategy is to define the Ca2+ signalling pathways in endothelial cells that impact on Weibel-Palade bod y trafficking and cell secretion.To this end I have discovered a new Ca2+-dependent G protein (Rab46) and assembled a body of evidence that provides an exciting novel perspective on the mechanisms underlying Weibel Palade body exocytosis (2018). My research will focus on the relationships between the G protein necessary for intracellular trafficking of WPBs and the spatial orientation of intracellular Ca2+ nanodomains. In addition, this research will uncover processes that could play important roles in other cellular systems pertinent to CVD such as pancreatic β cells and platelets.
This research has strategic relevance because despite advances in treatment, cardiovascular disease (CVD) remains the number one cause of death in the UK. This research opens the gateway for my future funding in understanding how these mechanisms are perturbed in diabetes and CVD. Clinically, there is a potential to enhance the treatment of CVD, especially in susceptible populations such as diabetics by manipulating selective WPB release.
Katarina T. Miteva1st, Lucia Pedicini1st, Lesley A. Wilson, Izzy Jayasinghe, Raphael G. Slip, Katarzyna Marszalek, Hannah J. Gaunt, Fiona Bartoli, Shruthi Deivasigamani, Diego Sobradillo, David J. Beech and Lynn McKeown. Rab46 integrates Ca2+ and histamine signaling to regulate selective cargo release from Weibel-Palade bodies. Journal Cell Biology. 2019. 218(7): 2232-2246.
- Faculty 1000Prime recommended 2019
Pedicini Lucia, Miteva Katarina, Appleby HA, Hawley V, Gaunt HJ, Cubbon RM, Marszalek K, Kearney MT, Beech DJ and Mckeown L. Endothelial homotypic Tunneling Nanotube formation induced by wheat germ agglutinin and thrombin. Scientific Reports. 2018 May 15;8(1):7569.
Rubaiy HN, Ludlow MJ, Henrot M, Gaunt HJ, Miteva K, Cheung SY, Tanahashi Y, Hamzah N, Musialowski KE, Blythe NM, Appleby HL, Bailey MA, McKeown L, Taylor R, Foster R, Waldmann H, Nussbaumer P, Christmann M, Bon RS, Muraki K, Beech DJ. Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels. J Biol Chem. 2017 292(20):8158-8173.
Li, J., Bruns, A., Hou, B., Rode, B., Webster, P.J., Bailey, M.A., Appleby, H.L., Moss, N.K., Ritchie, J.E., Yuldasheva, N., Tumova, S., Quinney, M., McKeown, L., Taylor, H., Prasad, K.R., Burke, D., O’Regan, D., Porter, K.E., Foster, R., Kearney, M.T., Beech, D.J. Orai3 surface accumulation and calcium entry evoked by vascular endothelial growth factor. ATVB 2015 35, 1987-1994.
Wilson LA 1st, McKeown L 1st, Tumova S, Li J, Beech DJ. A long variant of CRACR2A that belongs to the Rab GTPase protein family in endothelial cells. Biochem Biophys Res Commun. 2015 Jan 2;456(1):398-402Recent
- BSc. (Hons) Cell Biology
- Biochemical Society
- Physiological Society
- Fellowship of the HEA submitted Feb 2020
- Lecturer BHF 4yr Cardiovascular PhD students 2018 - present
- Supervisor Faculty Biological Sciences project students 2017 - present
- PhD 2/3rd year progress reviewer 2017 - present
- PhD 1st year transfer examiner 2016 - present
- Deputy coordinator MBChB Year 1 Introduction to Medical Sciences module 2015 - present
- Tutor MB ChB Year 1 Introduction to Medical Sciences module 2015 – present
- Supervisor BSc. Clinical Sciences intercalating medics 2014- present
- Co-supervisor 2x PhD students 2013 - 2017, School of Food Science
Research groups and institutes
- Leeds Institute of Cardiovascular and Metabolic Medicine
- Discovery and Translational Science
- British Heart Foundation - Cardiovascular research
- Multidisciplinary Cardiovascular Research Centre