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

Dr Timothy Millar BSc (Hons), PhD

Lecturer in Pharmacology

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

Research Focus : Lipid regulated angiogenesis, the vasculature as an adaptive immune cell modifier and cellular cross talk in microfluidic vascular models of infection and inflammation.

Context:

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 various aspects of endothelial function including:

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.

Collaborations with colleagues in engineering and microbiology make this research ideally suited to address complex problems in multicellular environments.

 

 

Qualifications

BSc (Hons) Biological Sciences, University of Birmingham (1992)
PhD, University of Bath (2000)
Postgraduate Certificate in Academic Practice, University of Southampton (2008)

Appointments held

Sep 2003 - Sep ’06 CIHR Postdoctoral Training Fellowship in Translational Research,
Immunology Research Group, University of Calgary, Calgary, Alberta, Canada.
Oxygen sensing, MAPkinase signalling and leukocyte recruitment to the endothelium during ischaemia reperfusion

Jan 2000, Jun ‘03 Postdoctoral Research Fellow
Bone and Joint Research Group, Department of Medical Sciences, University of Bath, Bath. Nitric oxide and peroxynitrite generation from xanthine oxidase, its various roles as an antibiotic and inflammatory mediator.

Aug 95 – Dec 99 PhD student,
Bone and Joint Research Unit,
University of London, London / Bone and Joint Research Group, University of Bath, Bath. Novel aspects of the activity and function of xanthine oxidase

Jan 94 - Jun 95 Research Assistant,
Coagulation Research, St Thomas’ Hospital, London. Fibrinogen binding to human melanoma cells and its effect on metastatic potential

Jan 93 – Dec 93 Research Assistant,
Biochemical Sciences, Wellcome Foundation Ltd, Beckenham, Kent. Neutrophil priming and secretion: signalling through phospholipase D

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.

 

Novel microfluidic devices for endothelial - epithelial cross talk.

The vascular endothelium lies in close contact with the epithelium lining the alveoli of the lung.  This allows for efficient gas exchange in respiration but is an important interface with the outside environment.  The epithelium is adept at forming a tight barrier to prevent external infiltration of noxious substances including infections in to the vasculature. This close abutment allows for signalling between the two cell types.  In particular, epithelial cells responding to an infection for instance can signal to the endothelium to recruit inflammatory cells.  In chronic respiratory diseases such as asthma, the epithelial – endothelial interaction is important to maintain an appropriate response.  Using microfluidic devices fitted with sensors we are investigating the cross talk between the two cell types in a model of inflammatory lung disease.  On infection, the epithelial barrier is compromised but can be re-established over time.  In our model of combined epithelial and endothelial cells we are able to observe a range of secreted cytokines from both cells types and that the barrier formed in co-cultures is significantly elevated above the monoculture in a synergistic manner.  We aim to develop this model to incorporate barrier and cytokine measurements and also to determine the role of inflammatory cell recruitment on these parameters in chronic asthma.

 

Department(s)

Clinical and Experimental Sciences

Affiliate Department(s)

Infection and Immunity Research group

  1. Postdoctoral supervision: Dr Dorota Bartczak, 2010 -2011
  2. Postdoctoral Supervision: Dr Vicky Humbert 2017
  3. PhD supervision: Dr Wen Chean Lim Completed 2015
  4. PhD supervision: Dr Michael Olding completed 2017
  5. PhD supervision: Dr Patience Brace completed 2017
  6. PhD supervision: Dr James Hewinson, completed 2005
  7. PhD supervision: Dr Emily Bennett completed 2006
  8. Current PhD students Miss Jemma Paterson Due 2019 / 20
  9. Current PhD student Miss Elisabetta Bottaro Due 2019 /20
  10. Current PhD Student Mr Jay James Due 2021
  11. Multiple undergraduate project research students
  12. Integrated PhD students project supervision - Miss Jo Underwood, Mr Alvaro Medina Barnuevo
University of Southampton

Member of Senate
Member of III Divisional Board
Member of AIR sub Divisional Board
Member of Princess Anne Tissue Collection Group

National and International responsibilities

STEM Ambassador – School Outreach

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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). London, GB: Chemical Rubber Company Press.
  1. Extensive teaching within the Faculty of Medicine on the BM5 and BM4 undergraduate Medicine course and cross Faculty in Biological Sciences including lectures, small group tutorials and practical sessions
  2. Module lead for the BM5 Gastrointestinal (GI) module
  3. Exam setting and marking of undergraduate and postgraduate (MSc) courses
  4. BM steering group committee member
  5. Personal Tutor
Dr Timothy Millar
Faculty of Medicine, University of Southampton, Building 85, Life Sciences Building, Highfield Campus, Southampton, SO171BJ

Room Number: SGH/LF73/MP825

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

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