August 10, 2018

Promovendus FHML/School for Cardiovascular Diseases/CARIM -Vaatchirurgie (4 years)

Research project: promotietraject op basis van CAVA-trial en aanverwante studie

De nadruk ligt op het opzetten en afronden van enkele vaatchirurgische studies met als eindproduct een promotie op basis van enkele (4-5) artikelen. Klinische werkzaamheden worden beperkt tot studiegerelateerde zaken welke niet door de dienstdoende (zaal)arts kunnen worden opgepakt (max 1-2 dagdelen/week). Primair: Voortzetten en afronden van CAVA-trial

Link tot academic transfer

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August 3, 2018

Promovendus FHML/School for Cardiovascular Diseases/CARIM -CARDIOLOGIE (4 years)

Research project: Microvasculaire functie bij hartfalen met behouden/preserved ejectie fractie (HFpEF)

De afdeling cardiologie zoekt een promovendus voor het onderzoeksproject “Microvasculaire functie bij hartfalen met behouden/preserved ejectie fractie (HFpEF)” Mannen en vrouwen zijn niet gelijk in de wereld van hartfalen. Hartfalen (HF) kan onderverdeeld worden in twee soorten: HF met verminderde/reduced ejectiefractie (HFrEF) of HF met behouden/preserved ejectiefractie (HFpEF).

Link tot academic transfer

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July 31, 2018

Position for PhD student FHML/School for Cardiovascular Diseases/CARIM -dept Pathology (4 years)

Research project: studies the role of hypoxia, inflammation and matrix turnover in atherosclerosis

The team is embedded in the Cardiovascular Research Institute Maastricht (CARIM) of Maastricht University Medical Center and studies the role of hypoxia, inflammation and matrix turnover in atherosclerosis. Atherosclerosis develops in the large arteries under the influence of high plasma cholesterol, hypertension and diabetes. Our group investigates the rupture of an atherosclerotic plaque, which is the actual cause of a myocardial infarct and / or stroke.

Link tot academic transfer

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June 8, 2018

PhD student CARIM, Physiology Bidirectional interaction of atrial electrophysiology and coagulation factors

The RACE-V network brings together researchers from Groningen, Maastricht and Leiden. Together, we are investigating how AF affects coagulation factors both in the blood and in atrial tissue and how these factors in turn alter the atrial tissue and lead to progression of AF.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. The risk of AF increases with age, and because the general population is ageing, the number of AF patients is expected to increase substantially in the coming decades. One of the most harmful consequences of AF is the formation of emboli that can lead to debilitating and life-threatening strokes. It is generally accepted that AF leads to changes in blood coagulation. However, we have recently demonstrated that alterations in coagulation factors can also contribute to the progression of AF. This bidirectional interaction between AF and coagulation is the main theme of the national network RACE-V ('Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilization in the Progression of AF', www.race-v.org), funded by the Dutch Heart Foundation. In this team, investigators from several disciplines, both basic scientists and clinicians, and various universities (Maastricht, Groningen and Leiden) collaborate. Our AF research group is part of CARIM, the CArdiovascular Research Institute Maastricht (www.carimmaastricht.nl). In this PhD project, the interaction between AF and coagulation will be studied in animal models of paroxysmal AF (i.e. intermittent episodes of AF) and heart failure. The disease mechanisms identified in these models can then be studied in atrial biopsies and blood samples collected in AF patients.

Link to Academic Transfer

 

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June 7, 2018

Project title: PhD studentship on vascular dementia research

Location: University of Birmingham (Institute of Inflammation and Ageing) & Maastricht University (CARIM, Cardiovascular Research Institute Maastricht)

Deadline: July 2nd 2018

Project description

White matter really matters in cerebral Small Vessel Disease: WNT signalling in the endothelial – oligodendroglial crosstalk

The PhD candidate will work at the interface between cardiovascular and neuro-sciences as part of a joint project between Maastricht University and the University of Birmingham. This project is focused on the crosstalk between endothelial cells and oligodendrocytes (OL) via WNT signalling in the context of cerebral small vessel disease (cSVD).

Neurodegenerative diseases represent a critical challenge to society due to population ageing, amongst which cSVD provides a promising area for therapeutic intervention because of its well-known cardiovascular risk factors (e.g. ageing, hypertension, diabetes). cSVD impairs cognitive function, and is characterized by the presence of lesions in myelin-rich white matter regions (WML) and Blood Brain Barrier (BBB) leakages, amongst other structural abnormalities. This indicates that oligodendrocytes (OL), the cells responsible for generating and supporting myelin, are especially vulnerable to injury in this condition. While the development of WML in cSVD is influenced by hypertension and other cardiovascular risk factors, specific mechanisms causing  WML have not been investigated.

The production of myelin during development places a major metabolic demand on OL and its precursors (OPCs) that must be satisfied by a sufficient blood supply. WNT signalling is critically important for developmental processes including blood vessel and blood brain barrier formation. It also mediates complementary actions to ensure the proper adjustment of OPC/OL function based on the oxygen and nutrients supply. The relevance of such mechanism in cSVD is unknown, but could explain the burden of WML and the presence of BBB leakages occurring from the newly formed, immature, leaky blood vessels.

In this project, the PhD student will study WNT signalling in OL/OPC, and its crosstalk with endothelial cells, to identify potential therapeutic strategies to limit BBB leakages and preserve myelin integrity in cSVD

Role description

·      Design and performs scientific research;

·      Works in a team with PhD students, scientists and clinicians;

·      Discuss plans and performs research in a stimulating environment;

·      Work in a highly international research group across two different sites: University of Birmingham and Maastricht University.

Requirements Applicants must be European residents, achieve the required University of Birmingham IELTS score (average 6.5 overall and no less than 6.0 in any one category), and be willing to spend 1.5 year in each University. The successful candidate will be registered as a PhD student at Birmingham University and will also be registered at Maastricht University. The graduation will result in a joint PhD degree from the two universities.

·Honours degree (2:1 or 1st class) in molecular life sciences, biomedical sciences, medical biology, neurosciences or a related discipline;

·Strong background in vascular and/or neuroscience research and/or pharmacology is an asset;

·Certification to work with animals and experience with conducting animal studies is an asset;

·Experience with cell culture work and molecular biology techniques is required;

·Highly motivated to work in an interdisciplinary environment;

·Excellent interpersonal and communication skills are essential;

·Willingness to work flexibly;

Your application must enclose the following information and documents:

• A detailed CV, including your nationality, country of birth and education;

• Names and addresses of two referees;

• A covering letter highlighting your research experience/capabilities;

• Copies of your degree transcripts;

• Evidence of your proficiency in English language.

Additional informations / contact Starting period: < November 2018

Full-time fixed-term employment for 3 years

Dr. Sébastien Foulquier, PhD, Dept of Pharmacology and Toxicology, CARIM, Maastricht University

Email: s.foulquier@maastrichtuniversity.nl

or

Dr. Daniel Fulton, PhD, Institute of Inflammation and Ageing, University of Birmingham

E-mail: D.Fulton@bham.ac.uk

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June 4,  2018
Joint PhD Maastricht University and University of Birmingham

Project title: The Tspan14/ADAM10 dyad: a major regulator of Notch signalling in atherosclerosis?

Supervisors: Dr Mike Tomlinson and Prof. Ed Rainger (Birmingham) and Dr Marjo Donners and Prof. Erik Biessen (Maastricht)

Type of opportunity: PhD (double doctorate)

Opportunity to be listed on: FindAPhD.com; jobs.ac.uk

Application deadline date: 02/07/18

Institution: University of Birmingham and Maastricht University

College/School: School of Biosciences (Birmingham) and CARIM School for Cardiovascular Diseases (Maastricht)

Contacts for enquiries

Mike Tomlinson

m.g.tomlinson@bham.ac.uk

Telephone +44 121 234 5678

Marjo Donners

marjo.donners@maastrichtuniversity.nl

Telephone +31 43 387 46 25

 

Project description (max 550 words)

Background

Atherosclerosis is the main underlying pathology of cardiovascular diseases and a leading cause of death worldwide.  It is a systemic, chronic inflammatory disease, triggered by various cardiovascular risk factors.  The ‘molecular scissor’ ADAM10 is expressed on all cells and cleaves the extracellular regions from its substrates which include Notch cell fate regulators.  We have shown that ADAM10 is expressed in human atherosclerosis, is associated with plaque neovascularization, and is causally involved in atherosclerotic plaque development in conditional ADAM10-knockout mice.  Specifically, macrophage ADAM10 deficiency promotes atherosclerotic plaque stability, by enhancing plaque fibrosis and reducing macrophage pro-inflammatory responses.  We have recently proposed that ADAM10 should not be regarded as a single scissor protein, but as six different scissors with distinct substrate specificities, depending on its association with one of six regulatory tetraspanins, Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 or Tspan33.

Hypothesis

Our recent unpublished data has led us to hypothesise that Tspan14/ADAM10 is a critical driver of macrophage and endothelial cell function in atherosclerosis via cleavage and activation of Notch.

This raises the exciting possibility of therapeutically targeting Tspan14/ADAM10 to promote plaque stability and prevent heart attack or stroke, without the toxicity that would result from targeting all six tetraspanin/ADAM10 complexes.

Aims

1. To determine the effect of Tspan14 knockdown on ADAM10 expression, localization and Notch activation in endothelial cells and macrophages in vitro.

2. To establish the impact of Tspan14 knockdown on endothelial cell and macrophage functions in vitro.

3. To investigate the role of macrophage and endothelial Tspan14 in inflammation and atherosclerosis.

Expected results

This project will provide important mechanistic insights into the regulation of ADAM10-Notch signalling by Tspan14 in two cells types that are highly relevant to inflammation and atherosclerosis, namely macrophages and endothelial cells.  The data will enable us to determine whether future therapeutic targeting of Tspan14 might improve specificity and reduce toxicity, compared to targeting either ADAM10 or Notch alone.

Funding notes (brief description of any specific funding available/eligibility requirements):

Applicants must be European residents, achieve the required University of Birmingham IELTS score (average 6.5 overall and no less than 6.0 in any one category), and be willing to spend the first year in Birmingham, the second year in Maastricht, and the third year in Birmingham or Maastricht.  The successful candidate will be registered as a PhD student at the University of Birmingham and will also be registered at Maastricht University. After successful PhD defence, the candidate will obtain a double doctorate in both UK and the Netherlands.

References (if required, you may include a small number of recent publications):

ADAM10-interacting tetraspanins Tspan5 and Tspan17 regulate VE-cadherin expression and promote T lymphocyte transmigration.  Reyat JS, Chimen M, Noy PJ, Szyroka J, Rainger GE, Tomlinson MG.  J Immunol 2017 199: 666-676.

Heterogeneity of atherosclerotic plaque macrophage origin, phenotype and functions: implications for treatment.  Nagenborg J, Goossens P, Biessen EAL, Donners MMPC.  Eur J Pharmacol 2017 816: 14-24.

Scissor sisters: regulation of ADAM10 by the TspanC8 tetraspanins.  Matthews AL, Szyroka J, Collier R, Noy PJ, Tomlinson MG.  Biochem Soc Trans 2017 45: 719-730.

Myeloid ADAM10 deficiency modulates atherosclerotic plaque composition by shifting the balance from inflammation toward fibrosis.  van der Vorst EP, Jeurissen M, Wolfs IM, Keijbeck A, Theodorou K, Wijnands E, Schurgers L, Weber S, Gijbels MJ, Hamers AA, Dreymueller D, Rose-John S, de Winther MP, Ludwig A, Saftig P, Biessen EA, Donners MM.  Am J Pathol 2015 185: 1145-1155.

Research hours available: Full time

Contacts for enquiries

Mike Tomlinson

m.g.tomlinson@bham.ac.uk

Telephone +44 121 234 5678

Marjo Donners

marjo.donners@maastrichtuniversity.nl

Telephone +31 43 387 46 25

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