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The University of Southampton
Medicine
Phone:
(023) 8120 8975
Email:
T.M.Millar@soton.ac.uk

Dr Timothy M Millar BSc (Hons), PhD, FHEA

Lecturer in Pharmacology

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Dr Timothy Millar is Lecturer in Pharmacology within Medicine at the University of Southampton.

The endothelium is a dynamic, specialised cellular structure that forms a selective barrier lining the luminal surface of the blood vessel. Our research focuses on stress responses in the endothelium during disease. Our research themes include:

These themes combine innate and adaptive immunity, infection and biofilm formation and pathophysiologic models to identify potential therapeutic targets. Using human cells and models that allow multiple cellular interactions and cross talk, we aim to study how diseases develop and the role of the endothelium in regulating the immune response, host pathogen interaction and pathologic angiogenesis.

Adaptation to environment and the response to stress is a theme that runs through my labs work. From low oxygen to lipid stress and pathogens to inflammatory cell recruitment, the endothelium plays a key role in responding rapidly to its local microenvironment.

The lab has expertise in the cell biology of endothelial cells including angiogenesis, migration and intracellular signalling. We develop microfluidic real time and time-lapse capability for visualising endothelial immune cell and endothelial pathogen interactions in collaboration with partners in Engineering.

We are actively engaged in expanding and refining our models to resemble normal physiology and disease in order to identify targets for intervention.

Qualifications

BSc (Hons) Biological Sciences, University of Birmingham (1992)
PhD, University of Bath (2000)

Appointments held

Lecturer in Pharmacology, “Wellcome Trust Value in People Award”, Faculty of Medicine, University of Southampton, UK

Previous appointments

CIHR Postdoctoral Training Fellowship Translational Research, Immunology Research Group, University of Calgary, Calgary, Alberta, Canada.  Oxygen sensing, MAPkinase signalling and leukocyte recruitment to the endothelium during ischaemia reperfusion

Postdoctoral Research Fellow Bone and Joint Research Group, Department of Medical Sciences, University of Bath, Bath, UK.

Nitric oxide and peroxynitrite generation from xanthine oxidase, its various roles as an antibiotic and inflammatory mediator.

Research Assistant, Haematology, Guys and St Thomas’ Hospital Trust. Fibrinogen cloaking in cancer cell haematogenous metastasis.

Research Assistant, Wellcome Plc, Phospholipase D signalling in neutrophil activation.

Research interests

Inflammation and regulatory T cell activation

The role of oxidized LDL and sphingosine-1-phosphate in angiogenesis

Lipids and their oxidized species are known to be important in a range of diseases especially cardiovascular disease.  We have shown that oxidized low density lipoprotein (oxLDL) can modulate angiogenesis. A complex picture has emerged with a biphasic response to oxidized lipids with physiologic concentrations of oxLDL stimulating angiogenesis, while at elevated, pathological levels of oxLDL, angiogenesis is prevented.  The mechanism for the elevated angiogenesis seems to rely on signalling via the bioactive lipid sphingosine-1-phosphate (S1P).  Using exogenous S1P and a range of receptor and sphingosine metabolic enzyme inhibitors, we have shown that angiogenesis to both oxLDL and S1P follows similar patterns.  High density lipoprotein (HDL) can potentially offset the effects of oxLDL while HDL itself can become oxidised. We are currently investigating the potential lipid receptor mediated control of oxLDl effects and the role of HDL, oxHDL and S1P in physiologic and pathologic angiogenesis.

 

The endothelium as an adaptive immune cell modifier regulating T cell proliferation and regulatory T cell activation

Inflammation is a natural response to noxious environmental stimuli but chronic inflammation can lead to compromised function.  The body has a mechanism to control the immune response using regulatory T cells that help to resolve inflammation and prevent inappropriate immune responses to self.  In chronic inflammatory disease the role of the regulatory T cell and the interaction with endothelium derived from different vascular beds is being studied to determine the mechanism of T cell activation via co-stimulatory molecules such as Programmed Death Receptor 1 (PD-1) and its ligand.  The endothelium has been shown to stimulate CD4+ T cell proliferation likely via antigen presentation while also activating the suppressive activity of Tregs. This study will further the understanding of endothelial adaptive immune cell control and lead to potential new therapeutics for T reg activity in the chronic inflammation and cancer.

 

Vasculature on-a-chip platforms for peripheral venous disease and infective endocarditis research

Peripheral vascular disease can lead to a reduced flow of blood to the extremities that, left untreated, can cause ulcers of the skin with ischaemic damage to surrounding tissue, infection that might become systemic and may require amputation.  Causes include vascular spasm and arteriosclerosis that may also lead to blood clots that block perfusion of the limbs.  Sclerotherapy involves the injection of compounds into the vasculature to treat venous malformations and varicose veins. The vessels become occluded when the sclerosant removes the endothelial lining of the blood vessel that in time resorbs the damaged vessel and encourages new blood vessel formation. Embolotherapies try to occlude abnormal blood vessels such as in aneurysms, vascularised tumors and vascular malformations. Embolotherapies can also be used to cause cerebral revascularization by reopening occluded or narrowed normal vessels. Our research is using novel microfluidic devices that mimic in vivo blood vessel architectures to initially test methods for endovascular therapies.

 

Host pathogen interactions in the formation of vegetations in infective endocarditis and the design of novel antifouling replacement heart valves

Endocarditis is an inflammation of the inner lining of the heart and commonly involves the valves. Vegetations form that can be sterile and non-infective or caused by bacterial colonisation of the endocardium. There are increasing numbers of cases associated with prosthetic valves and hospital acquired infections (20 – 30% of all cases), with considerable one year mortality (25%). Common infective agents are Staphylococcus aureus and Streptococcus spp. that form vegetations with platelets and inflammatory cells around heart valves and can embolise blood vessels causing myocardial infarction, stroke and disseminated intravascular coagulopathy (DIC). This damage eventually requires the patient to undergo a replacement procedure. Biological valves are derived from bovine or porcine pericardium whereas mechanical valves are made from metals and often Teflon coated. Although longer lived than biological valves, mechanical valves require the patient to take life-long anticoagulants to prevent thrombosis.

Our aims are to develop biomimetic microfluidic devices within which we will (i) utilise the host – pathogen interaction to determine therapeutic targets (ii) test technologies to understand the role of flow dynamics on biofouling and (iii) test biocompatible materials for bioengineered antifouling replacement heart valves.

 

Department(s)

Clinical and Experimental Sciences

Affiliate Department(s)

Infection and Immunity Research group

PhD supervision

Dr James Hewinson completed 2005

Dr Emily Bennett completed 2006

Dr Wen Chean Lim Completed 2015

Dr Michael Olding completed 2017

Dr Patience Brace completed 2017

Dr Elisabetta Bottaro 2019

Dr Jemma Paterson completed 2020

Current Mr Jay James Due 2021

Current Mr Alireza Meghdadi Due Dec 2021

Other responsibilities

  • Network for Anti-Microbial Resistance and Infection Prevention, Committee member, University of Southampton
  • Academic Appeals Assessor, Faculty of Medicine
  • Academic integrity officer, Faculty of Medicine
  • University of Southampton Core values working group June 2013
  • University of Southampton Academic promotions and probations working group 2012 -2013
  • University of Southampton Senate Representative – School of Medicine 2007 – 2011
  • PCAP Mentor
  • Postdoctoral mentor
  • Postgraduate and undergraduate research project student supervisor
  • Undergraduate “Inspire” academic network
  • Southampton Academic Society mentor
  • Peer teaching training day facilitator
  • British Microcirculation and Vascular Biology Society, Committee Member
  • Chair, British Microcirculation and Vascular Biology Society Annual meeting, Southampton 2020
  • Science Engineering Technology and Maths (STEM) Ambassador
  • “I’m a scientists, get me out of here”, contestant
  • British Science week, presenter, “the most dangerous game in the world”
  • Manuscript reviewer
  • Grant reviewer (BBSRC)
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Articles

Book Chapter

  • Bodamyali, T., Kanczler, J. M., Millar, T. M., Stevens, C. R., & Blake, D. R. (2003). Free radicals in rheumatoid arthritis: Mediators and modulators. In L. Packer, M. Podda, & J. Fuchs (Eds.), Redox-Genome Interactions in Health and Disease (pp. 591-611). (Oxidative Stress and Disease). Chemical Rubber Company Press.
  • Lecturer in Pharmacology, Faculty of Medicine, BMBS undergraduate course
  • Assessments lead, Faulty of Medicine, BMBS (Year 2)
  • Pharmacy and Pharmacology Head of Field, undergraduate projects, Faculty of Medicine, BMBS (Year 3)
  • Medical undergraduate personal academic tutor
  • Committee memberships
  • Faculty of Medicine Year 1 and 2 Batchelor of Medicine steering group
  • Faculty of Medicine BMBS all Years assessment group

Previously

  • GI Module lead, Faculty of Medicine, BMBS (Year 2)
  • Foundations of Medicine module lead, Faculty of Medicine, BMBS (Year 1)
Dr Timothy M Millar
Faculty of Medicine, Room AB215, Mailpoint 801, South Academic Block, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD

Room Number: SGH/LF73/MP825

Telephone:(023) 8120 8975
Email:T.M.Millar@soton.ac.uk

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