Dr Lynn McKeown

Profile

Education

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

Research

2020 – present    Associate Professor in Vascular Cell Biology, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), School of Medicine, University of Leeds

2015 – 2020         University Academic Fellow in cardiovascular biology, 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, 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

Funding

• 3 yr BHF Non-Clinical PhD studentship. £181,000. (PI). March 2022 – March 2025. Investigating Rab46-dependent mechanisms underlying selective release of cargo from Weibel-Palade bodies
• 4 yr BHF Non-Clinical PhD Studentship. £170,000. (PI). Sept 2021- Sept 2025. The effect of diabetes on Weibel-Palade body function
• BBSRC 20Alert. Lattice Light Sheet Microscopy for the Biosciences. £771,000. (Co-A) 01/08/2021
• Royal Society Project Grant. RGS\R2\202259. £18,602. (PI). March 2021 – March 2022. Developing tools for the study of a novel Rab GTPase.
• 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

Responsibilities

• Principal Investigator
• Lecturer in School of Medicine

Research interests

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.

Recent Publications:

2021:

Dapeng Wang, Ashley Money, Lucia Pedicini, Sabina Wiktor, Asya Carlton, Alex Breeze and Lynn McKeown. Association of Rab46 polymorphisms with Covid-19 fatality. MedRxiv. 

Pedicini L, Wiktor SD, Simmons KJ, Money A, and McKeown L. Affinity-based proteomics reveals novel binding partners for Rab46 in endothelial cells. Sci Rep. 2021 Feb 8;11(1):4054.

2019:

Katarina T. Miteva^1st, Lucia Pedicini^1st, Lesley A. Wilson, Izzy Jayasinghe, Raphael G. Slip, Katarzyna Marszalek, Hannah J. Gaunt, Fiona Bartoli, Shruthi Deivasigamani, Diego Sobradillo, David J. Beech and Lynn M^cKeown.  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

2018:

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.

2017:

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.

2015:

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

Qualifications

• PhD
• BSc. (Hons) Cell Biology

Professional memberships

• Biochemical Society
• Physiological Society
• European Calcium Society

Student education

Teaching

• Research module developer MSc. Cardiovascular Biology
• Research Module lead International PhD programme
• Internal PhD examiner
• Fellow of the Higher Education Academy
• 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 1^st year transfer examiner 2016 - present
• Deputy coordinator MBChB Year 1 Introduction to Medical Sciences module 2015 - 2021
• Tutor MB ChB Year 1 Introduction to Medical Sciences module 2015 – 2021
• 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