Research Focus
The research focus of my group is to understand the mechanism of endothelial dysfunction in pulmonary hypertension. The objective of this work is to develop new therapeutic strategies for the treatment of this disease. To achieve this we use data from proteomic, genomic and metabolomic screening of pulmonary hypertensive patient samples available in our Centre. This allows us to identify signalling mediators linked to endothelial dysfunction. We also manipulate the expression levels and activity of selected protein targets in cultured pulmonary vascular cells in order to verify their role in pulmonary vascular remodelling.
Drawing inspiration from advances in computer processing, our group, together with the group of Professor Joshua Edel (Department of Chemistry, ICL), have produced pulmonary artery-on a-chip, a three dimensional model of a living, muscularised human lung blood vessel on a microchip.
The device contains a series of microscopic chambers separated by a thin porous membrane. Endothelial cells are grown on one side and smooth muscle cells on the other. Nutritious medium is continuously pumped over the endothelial cells, effectively mimicking the flow of blood inside a vessel. By taking blood and cells from pulmonary hypertensive patients, we aim to recreate disease conditions inside the microchip. The device also aims to create a highly controlled environment for multiple drug testing and reduce, or even eliminate, the experimental use of animals.
Our group were first to demonstrate that deficiency of oxygen and nitric oxide is a key factor in the disease process, inducing pulmonary endothelial barrier dysfunction and abnormal angiogenic responses as a result of an imbalance in the activation of actin cytoskeleton regulators, Rho GTPases: RhoA and Rac1.
We have identified another Rho GTPase, RhoB which is involved in pulmonary vascular remodelling. RhoB regulates actin polymerisation and the intracellular trafficking of growth factor receptors in pulmonary endothelial and smooth muscle cells. Prenylation (the addition of hydrophobic molecules, farnesyl or a geranyl-geranyl moiety to the C-terminal cysteine(s) of the target protein) of RhoB is required for its membrane localization and activation. We have identified an effective strategy of pharmacological targeting of RhoB by drugs used in the treatment of cancer, farnesyltransferase inhibitors. We show that these inhibitors may exert better control over disease-related increases in Rho proteins expression and activity than general prenylation inhibitors, statins.
Fig. 1. Overexpression of geranylgeranylated RhoB induces stress fibre formation in human pulmonary artery endothelial cells (HPAECs). GG-RhoB (blue), F-actin (red). Bar=10µm.
We have recently identified a novel pathway regulating membrane trafficking and the stability of bone morphogenetic protein receptor II (BMPRII) in pulmonary endothelium involving Arf family of proteins. We show that activation of one member of this family, Arf6 inhibits membrane recycling of BMPRII and prompts proteolytic degradation of the receptor. Inhibition of Arf6 activity with cytohesin inhibitors, such as SecinH3, restores BMPRII expression and reduces inflammatory responses in cultured endothelial cells and the lungs of animal models of pulmonary hypertension and prevents development of the disease in preclinical models of PAH. This work identifies a new class of pharmacological targets in PAH. It also provides an important insight into basic biological mechanisms responsible for the regulation of localization and stability of membrane receptors.
Figure 2. Trajectories of YFP-GGA1 (yellow fluorescent protein–labelled golgi-associated, gamma adaptin ear-containing, ARF-binding protein 1) vesicles in CLIC4-overexpressing human pulmonary artery endothelial cells (HPAECs). Bar=2µm. (Circ Res 2019)
Most recent studies focus on therapeutic role of exosomal microRNAs from endothelial cells overexpressing Kruppel Like Factor 2 (KLF2), a flow-induced transcription factor. Discovery of KLF2 mutation in patients with hereditary pulmonary arterial hypertension (HPAH) may be of significance, as KLF2 is a key regulator of endothelial homeostasis in the lung. Delivery of KLF2-induced exosomes or exosomal miRNAs represents a promising therapeutic strategy in PAH.
Some other past projects in my groups also involved therapeutic targeting of enzymes increasing nitric oxide bioavailability, DDAH; the role of neutrophils in pulmonary endothelial and smooth muscle activation and vascular remodelling in pulmonary hypertension and therapeutic potential of endothelium-derived microparticles in pulmonary hypertension.
Research Group
Pulmonary Vascular Biology Group
PhD Students:
Salina Nicoleau; salina.nicoleau14@imperial.ac.uk
Maike Haensel; maike.haensel18@imperial.ac.uk
Rehab Alharbi; r.alharbi20@imperial.ac.uk
Alexander Ainscough; alex.ainscough14@imperial.ac.uk
Hebah Sindi; h.sindi14@imperial.ac.uk
Mai Alzaydi; m.alzaydi15@imperial.ac.uk
Tim Smith; tahjsmartguy@gmail.com
Lucio Iannone; l.iannone@imperial.ac.uk
Lulwah Aldabbous; l.aldabbous12@imperial.ac.uk
Lisa Storck; lisa.storck@imperial.ac.uk
Post-Docs:
Dr Adam Fellows; a.fellows@imperial.ac.uk
Dr Sandro Satta
Dr Giusy Russomanno; g.russomanno@imperial.ac.uk
Dr Vahitha Abdul-Salam; vahitha.abdul-salam02@imperial.ac.uk
Dr Lucie Duluc; l.duluc@imperial.ac.uk
Dr Hilda Tsang
If you are interested in joining my research group, please contact me by email (b.wojciak-stothard@imperial.ac.uk ), enclosing a CV, short description of your research experience to date and proposed source of funding for your work (if applicable).
MSc student supervision
Rachel Hayley MSc in Molecular Medicine (Feb 2020-August2020)
Salina Nicoleau MSc in Molecular Medicine (Feb 2020-August 2020)
Pei Haoyu MRes in Translational Medicine (Oct 2018-Sept 2019)
Angelos Glynos MRes in Translational Medicine (Oct 2017-September 2018)
Kyeong Beom Jo MSc in Molecular Medicine (Feb 2018-August 2018)
Ahmed Osman MRes in Translational Medicine (Oct 2016-September 2017)
Abdul Mahomed MRes in Translational Medicine (Oct 15-Aug 16)
Sara Fonseca MSc in Molecular Medicine (Feb-August 2015)
Daria Belik MSc in Molecular Medicine (February – August 2013)
Dogukan Dalgalan MSc in Molecular Medicine (February–August 2012)
Wu Yixing MSc in Molecular Medicine (February-August 2011)
Andia Redpath MRes in Biomedical research, BMR stream October 2010 – May 2011
BSc student supervision
Miu Shing Hung BSc in Biomedical Sciences (Nov 2020-April 2021)
Nayana Iyler BSc in Biomedical Sciences (Nov 2019-April 2020)
Aditya Vijay BSc project (Haematology) (Feb –May 2019)
Jasraj Panesar BSc project (Haematology) (Feb-May 2015)
Veidika Chohan BSc project (Haematology) (February – May 2014)
Kim Dain BSc project (Haematology)(February – May 2014)
Dexter Valencia BSc project (Haematology) (February –May 2012)
Kirupananthan Thanighan BSc project (Haematology) (February –May 2012)
Wing kin Liu BSc project (Haematology) (February –May 2012)
Ahmed Syed BSc project (Haematology) (March- May 2010)
Collaborators
Prof. Soni Pullamsetti, Max Planck Institute for Heart and Lung Research, Germany., Collaborative work on the role of KLF2 signaling in pulmonary hypertension., 2017
Professor C Bernabeu, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain., endoglin, vascular biology, 2014 - 2016
Mark Toshner, Pulmonary Vascular Diseases Unit, Papworth Hospital NHS Foundation Trust, Papworth, Everard Cambridge, United Kingdom, vascular biology, 2013 - 2017
Professor John C Edwards, Department of Internal Medicine, St. Louis University, St. Louis MO, 2012 - 2016
Professor Stuart Yuspa, Centre for Cancer Research, Bethesda, MD, USA, chloride intracellular channel proteins, 2012 - 2016
Professor Kurt Stenmark, University of Colorado Denver Health Sciences Center, Aurora, 2012 - 2016
Professor Jane Mitchell, Department of Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, vascular biology, 2011 - 2016
Dr James Leiper, MRC Clinical Sciences Centre, Imperial College London, DDAH, vascular biology, nitric oxide, 2006 - 2016
Professor Hans-Joachin Schnittler, Institute of Anatomy and Vacular Biology, Munster University, Germany, 2005
Guest Lectures
Cambridge University - Kruppel-like factor 2 signalling in pulmonary arterial hypertension/or endothelial dysfunction in PAH, Cambridge University, Department of Pharmacology, 2020
Queen's University, Belfast - Endothelial microRNAs and pulmonary arterial hypertension, Wellcome-Wolfson Institute for Experimental Medicine, Seminar Series, Queen’s University Belfast, 2020
IVBM Seoul, Korea -Therapeutic Role of Endothelial microRNAs in Pulmonary Arterial Hypertension, International Vascular Biology Organization, Seoul, Korea, 2020
EVBO -Therapeutic Potential of Endothelial microRNAs in Pulmonary Arterial Hypertension, 1st webinar European Vascular Biology Organization, 2020
Fukuoka, Japan. Shear stress-induced microRNAs: implications for treatment of pulmonary hypertension, 8th Annual World Congress of Molecular & Cell Biology, Fukuoka, Japan, 2018
Cambridge University: Exosomal KLF2-induced microRNAs: implications for treatment of pulmonary hypertension, Cambridge University, Cardiovascular Biology Seminar Series,, 2018
PVRI, Singapore. Exosomal KLF2-induced miRNAs in treatment of pulmonary hypertension, Annual World Congress of Pulmonary Vascular Research Institute in, Singapore, 2018
Role of chloride intracellular channel protein 4 in pulmonary vascular remodeling, 10th World Congress for Microcirculation, Kyoto, Japan, 2015
International CLIC4 meeting guest lecture:, Centre for Cancer Research, Bethesda, MD, USA, 2015
RhoB is the regulation of endothelial dysfunction in pulmonary hypertension. Cardiovascular Biology Seminars., Clinical School, Cambridge University, 2013
Rho GTPases in the regulation of endothelial function, Nencki Institute, Polish Academy of Sciences, Warsaw, Poland, 2012
Rho GTPases in the regulation of pulmonary vascular function, 6th European Vascular Biology Meeting, 2011
Vascular endothelium: Role in disease pathogenesis and as a terapeutic agent: Rho GTPases in the regulation of endothelial function, Imperial College London Vascular Biology Symposium, 2008
Hypoxia, ischaemia and infarction: An Update. Cellular mechanisms underlying hypoxic damage., Fellowship of Postgraduate Medicine. Medical Society of London., 2007
Cardiovascule Medicine Seminar Series: Rho GTPases in endothelial responses to hypoxia, King's College London, 2006
Rho GTpases in endotelial responses to hypoxia, Grover Conference on Pulmonary Circulation, Denver, Colorado, 2006
Regulation of endothelial polarity and migration under shear stress, Cell Motility Club, LMCB, UCL, 2003
Research Staff
Abdul-Salam,V
Ainscough,A
Duluc,L
Fellows,A
Russomanno,G
Tsang,H
Research Student Supervision
Aldabbous,L, The Role of Neutrophil Extracellular Traps (NETs) in the pathogenesis of Pulmonary Hypertension (PH)
Belik,D, Endoglin+ endothelium-derived microparticles in endothelial dysfunction in pulmonary hypertension
Chohan,V, The effects of RhoB prenylation modification on pulmonary artery endothelial cells exposed to hypoxia
Dagalan,D, Microparticles and endothelial dysfunction in pulmonary hypertension
Dain,K, The role of Chloride Intracellular Channel 4 in the regulation of leukocyte adhesion to the pulmonary endothelium
Iannone,L, ADMA METABOLISM AND CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION
Liu,WK, The role of RhoA-induced microparticles in the regulation of pulmonary endothelial function in vitro
Mahomed,A, ROLE OF CHLORIDE INTRACELLULAR CHANNEL 4 IN THE REGULATION OF INFLAMMATORY RESPONSES IN PULMONARY VASCULAR ENDOTHELIUM
Panesar,J, The Role of NETs in Pulmonary Endothelial Dysfunction: a potential player in the pathogenesis of PH
Redpath,A, cGMP in the regulation of pulmonary endothelial function
Sindi,H, Therapeutic role of exosome-mediated gene delivery in pulmonary hypertension (PH)
Storck,L, Profiling Protein Prenylation Using a Quantitative Chemical Proteomics Approach
Syed,A, RhoB in regulation of pulmonary endothelial cell responses to hypoxia
Thanighan,K, Potential therapeutic intervention for pulmonary hypertension — making cells talk to each other
Topp,SF, The effect of Tipifarnib on VEGF-induced pulmonary endothelial angiogenesis
Valencia,D, The role of chloride intracellular channel 4 in nuclear factor kappa B- mediated inflammation in Pulmonary Arterial hypertension
Yixing,W, Role of RhoB in the Regulation of Pulmonary Endothelial Responses to Hypoxia