vascular

vascular

Vascular biology and haemostasis

Heart attack and stroke are the world’s biggest killers, accounting for over 15 million deaths every year worldwide. They are also major health challenges locally, as the Yorkshire and Humber region has one the highest death rates from cardiovascular disease in the UK.

Using cutting-edge molecular and cellular biology, our research focuses on the function of platelets, the small blood cells that form clots, and the endothelium, the inner layer of cells that directly contacts circulating blood.

Through external links and inter-disciplinary collaborations with groups in Biomedical Sciences at the University of Hull, our research is identifying new targets to develop innovative treatments to improve outcomes for patients with cardiovascular disease.

Projects

The role of zinc in platelet biology

Title: The role of zinc in platelet biology
Timeframe: 2017-2020
Funder: University of Hull
Contact: Dr Simon Calaminus

The purpose of this project is to investigate how zinc helps to control the cell signalling that leads to platelet activation.  Control of these signalling pathways is critical to effective activation of the platelet.

In the blood there cells called platelets. When the body sustains a cut, the platelet activates, becomes very sticky and forms a platelet aggregate that seals the cut. A metal called zinc is used to help platelets activate and we are investigating the processes by which zinc changes platelet function.

The role of cyclic nucleotides in the control of RhoGTPases

Title: The role of cyclic nucleotides in the control of RhoGTPases
Timeframe: 2016-2019
Funder: University of Hull
Contact: Dr Simon Calaminus

RhoGTPases are very important proteins involved in the control of platelet shape and function. Understanding the cell signalling that changes their activity levels is therefore key to understanding how this affects platelet function.

When you bleed platelets stick together (aggregate) and stop the bleeding. This process is critical as if the platelet aggregate is too big it can block a blood vessel, potentially causing a stroke or heart attack. This project investigates how changing the blood vessel environment can affect platelet aggregate formation.

Outputs

Yusuf, M. Z. et al. Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability. Sci Rep 7, 5582, doi:10.1038/s41598-017-05817-9 (2017).

Atkinson, L. et al. Reversal of stress fibre formation by Nitric Oxide mediated RhoA inhibition leads to reduction in the height of preformed thrombi. Sci Rep 8, 3032, doi:10.1038/s41598-018-21167-6 (2018).

ThrombiGlow: ‘Smart’ Multimodal Platelet Specific ‘Theranostic’ Drug Delivery Imaging Agents

Title: ThrombiGlow: ‘Smart’ Multimodal Platelet Specific ‘Theranostic’ Drug Delivery Imaging Agents
Timeframe: February 2017 - February 2020
Funder: British Heart Foundation
Contact: Dr Simon Calaminus and Dr Graeme Stasiuk (University of Hull)

This project is designed to create a novel drug delivery system that will bind to platelets and no other cell type in the body. The aim is to therefore reduce non-specific effects of the therapy, minimising side-effects experienced by the patient.

When you bleed platelets stick together (aggregate) and stop the bleeding. Unfortunately in Cardiovascular Disease platelets can activate even if there is no cut, causing serious health issues, such as heart attacks.  This project will develop a platelet specific drug delivery system to reduce patient side-effects.

The metabolism of blood platelets

Title: The metabolism of blood platelets
Timeframe: 2018-2021
Funder: University of Hull
Contact: Dr Roger Sturmey and Lloyd Atkinson

The purpose of this project is to investigate the metabolic and biochemical regulation of platelets in health and disease.

Blood platelets are fundamental for haemostasis and thrombosis, yet we know remarkably little about how they fuel their functions – and even less about how this is regulated in disease states.  By understanding the changes in platelet metabolism in health and disease we hope to be able to elucidate new therapeutic targets.

Outputs

Aibibula M, Naseem KM, Sturmey RG.  2018.  Glucose metabolism and metabolic flexibility in blood platelets.  Journal of Thrombosis and Haemostasis.  In press doi: 10.1111/jth.14274

α-synuclein is a novel regulator of platelet function

Title: α-synuclein is a novel regulator of platelet function
Timeframe: Ongoing
Funder: Hull York Medical School
Contact: Dr Ahmed Aburima

The aim of this project is to identify the role of α-synuclein in regulating platelet function.

α-synuclein is a protein that is critical for the transmission of nerve signals. Hence platelets bear similarities to neurons in term of their secretion machinery, we examined platelet function using mice that are deficient of α-synuclein. Our data suggest that α-synuclein plays a supportive role in secretion. 

Chronic kidney disease predisposes patients to develop cardiovascular complications

Title: Chronic kidney disease predisposes patients to develop cardiovascular complications
Timeframe: Ongoing
Funder: Hull York Medical School
Contact: Dr Ahmed Aburima

The aim of this project is to identify the effect of uremic toxins on platelet function.

Patients with chronic renal failure frequently show complex haemostatic disorders, most frequently bruising and bleeding, suggesting a platelet defect. Indoxyl sulphate, an un-dialyzable toxin, contributes to impaired platelet function. In this project, we examine platelet function under conditions that resemble those in people with kidney failure.

Proinflammatory and prothrombotic platelets as non-invasive markers for disease progression

Title: Proinflammatory and prothrombotic platelets as non-invasive markers for disease progression.
Timeframe: Ongoing
Funder: Hull York Medical School
Contact: Dr Ahmed Aburima

The aim of this project is to identify platelet biomarkers that are highly predictive for diagnosing and monitoring disease progression.

Platelets contribute to the body’s immune response to infection and cancer due to their intrinsic tendencies to recruit leukocytes to sites of infection and the ability to interact with cancer cells. This is fuelled by a repertoire of cytokines and receptors within platelets identifiable by flow cytometric analysis, which makes them ideal biomarker source for disease monitoring.

Coronin is a negative regulator of platelet spreading and thrombus formation

Title: Coronin is a negative regulator of platelet spreading and thrombus formation 
Timeframe: 2016-2019
Funder: British Heart Foundation
Contact: Dr Francisco Rivero

The purpose of this project is to investigate in detail how the cytoskeleton regulator coronin controls the activation of blood platelets and help design better drugs to treat conditions like heart attacks and stroke.

We think that the scaffold protein coronin stops platelets from becoming too sticky and reduce the risk of people having heart attacks. To investigate that we use platelets taken from the blood of mice that do not contain coronin. We will study in detail how these altered platelets form blood clots and how this is different from clots formed by normal platelets.

Outputs

P. Joshi, D. R. J. Riley, J. S. Khalil, H. Xiong, W. Ji, F. Rivero. The membrane-associated fraction of cyclase translocates to the cytosol upon platelet stimulation. Scientific Reports, 8:10804 (2018)

Platelets as elements of the immune system against bacterial infection

Title: Platelets as elements of the immune system against bacterial infection
Timeframe: 2016-2019
Funder: University of Hull
Contact: Dr Francisco Rivero

The purpose of this research is to investigate the molecular mechanisms that platelets employ to migrate towards chemoattractants and bacteria and to collect and potentially uptake pathogens.

The role of platelets in helping sealing blood vessel injuries to prevent bleeding is widely studied but less is known about their role scanning the circulating blood to capture bacteria and prevent infections. We explore the mechanisms that platelets use to move towards areas of infection.

Molecular regulators of endothelial cell barrier function in cardiovascular disease

Title: Molecular regulators of endothelial cell barrier function in cardiovascular disease
Timeframe: 2018-2021
Funder: University of Hull
Contact: Dr Francisco Rivero

The purpose of this research is to investigate the molecular mechanisms of MYPT1, the regulatory subunit of the myosin light chain phosphatase. This is a component of a signalling pathway that regulates the cytoskeleton motor protein myosin and ensures the maintenance of the endothelial cell barrier.

Stress commonly affects key events that ensure the maintenance of the blood vessel barrier. One of these events modulates the activity of myosin, a protein used by the cell to generate force. This regulation requires molecular modifications that alter myosin’s function. MYPT1 participates in those modifications but its role in the blood vessel barrier is poorly understood.

Novel cardiovascular markers and therapies based on arginine methylation

Title: Novel cardiovascular markers and therapies based on arginine methylation
Timeframe: 2018-2021
Funder: University of Hull
Contact: Dr Francisco Rivero and Dr Pedro Beltran-Alvarez

This collaboration explores the relevance of the post-translational protein modification arginine methylation  in platelet function and the potential of its inhibition as an antiplatelet therapeutic intervention.

Platelets have a complex system of communication to help clump together. We have seen that platelets where one of these communication routes (arginine methylation) is blocked stop clumping. We investigate why arginine methylation is important for platelet function. Blocking this route could become a form of medication for people at risk of heart attacks or strokes.

 

Identifying the molecular basis for re-purposing diabetes medicines for management of myeloproliferative neoplasms (MPNs)

Title: Identifying the molecular basis for re-purposing diabetes medicines for management of myeloproliferative neoplasms (MPNs)
Timeframe: Ongoing
Funder: British Heart Foundation and Diabetes UK
Contact: Professor Tim Palmer

We have identified a new mechanism by which an intracellular switch called AMP-activated protein kinase (AMPK) inhibits the function of constitutively active JAK2V617F protein responsible for disease in many patients with MPNs. Based on this observation, we believe AMPK-activating drugs currently used in the clinic to manage type 2 diabetes could also be used (or “re-purposed”) to reduce bleeding complications in MPN patients.

Bleeding complications negatively impact the quality of life and life expectancy of patients with MPNs, a group of three related blood cancers. We have identified a new mechanism by which a widely prescribed class of drugs currently used to treat type 2 diabetes can inhibit a critical cellular pathway in blood vessel walls responsible for bleeding complications in MPN patients. By understanding the molecular mechanisms responsible, we will examine the potential for using these drugs to manage bleeding complications effectively in MPN patients.

Outputs

Rutherford C, Speirs C, Williams JJ, Ewart MA, Mancini SJ, Hawley SA, Delles C, Viollet B, Costa-Pereira AP, Baillie GS, Salt IP, Palmer TM. Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling. Sci Signal. 2016 Nov 8;9(453):ra109.

Mancini SJ, White AD, Bijland S, Rutherford C, Graham D, Richter EA, Viollet B, Touyz RM, Palmer TM, Salt IP. Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation. Mol Cell Endocrinol. 2017 Jan 15;440:44-56. doi: 10.1016/j.mce.2016.11.010.

Speirs C, Williams JJL, Riches K, Salt IP, Palmer TM. Linking energy sensing to suppression of JAK-STAT signalling: A potential route for repurposing AMPK activators? Pharmacol Res. 2018 Feb;128:88-100. doi: 10.1016/j.phrs.2017.10.001.

 

Mancini SJ, Boyd D, Katwan OJ, Strembitska A, Almabrouk TA, Kennedy S, Palmer TM, Salt IP. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci Rep. 2018 Mar 27;8(1):5276. doi: 10.1038/s41598-018-23420-4.

New treatments to improve patient outcomes after stenting and bypass surgery

Title: New treatments to improve patient outcomes after stenting and bypass surgery 
Timeframe: Ongoing
Funder: British Heart Foundation and University PhD scholarship
Contact: Professor Tim Palmer

Many patients with coronary heart disease undergo revascularisation procedures (stenting or bypass surgery) to restore blood flow to the heart. However these procedures often fail due to re-narrowing (or restenosis) of the blood vessel, meaning that symptoms re-occur.

As there are currently no effective pharmacological treatments, our purpose is to identify new molecular targets to prevent restenosis to improve outcomes for patients.

Coronary heart disease (CHD) caused by narrowing or blockage of the coronary artery is responsible for over 60,000 deaths every year in the UK. Importantly surgical treatments fail in a large number of patients due to abnormal thickening and re-narrowing of the affected blood vessel. Our aim is to develop new medicines to prevent vessel re-narrowing and improve outcomes for patients with CHD.

Outputs

Rutherford C, Childs S, Ohotski J, McGlynn L, Riddick M, MacFarlane S, Tasker D, Pyne S, Pyne NJ, Edwards J, Palmer TM. Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1. Cell Death Dis. 2013 Nov 21;4:e927. doi: 10.1038/cddis.2013.455.

Williams JJ, Munro KM, Palmer TM. Role of Ubiquitylation in Controlling Suppressor of Cytokine Signalling 3 (SOCS3) Function and Expression. Cells. 2014 May 30;3(2):546-62. doi: 10.3390/cells3020546.

Williams JJL, Alotaiq N, Mullen W, Burchmore R, Liu L, Baillie GS, Schaper F, Pilch PF, Palmer TM. Interaction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stability. Nat Commun. 2018 Jan 12;9(1):168. doi: 10.1038/s41467-017-02585-y.

Speirs C, Williams JJL, Riches K, Salt IP, Palmer TM. Linking energy sensing to suppression of JAK-STAT signalling: A potential route for repurposing AMPK activators? Pharmacol Res. 2018 Feb;128:88-100. doi: 10.1016/j.phrs.2017.10.001.

 

Moshapa FT, Riches-Suman K, Palmer TM. Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus. Cardiol Res Pract. 2019 Jan. doi: 10.1155/2019/9846312