Medicine

Timothy Millar

BSc (Hons), PhD

Primary position:
Lecturer in Pharmacology

Background

The University of Southampton
Research Focus : Cell trafficking and angiogenesis in inflammation and cancer

Context:

Inflammation is a required consequence of infection to return the body to homeostasis. Inappropriate inflammation can lead to compromised function. Conversely, in the surveillance of self, the immune system requires the ability to discern normal tissue from malignancy. The trafficking of immune cells into tissue follows a cascade of events and signals and the decision to initiate or regulate inflammation is controlled by the local microenvironment. The vascular endothelium plays a major role in the control of cell trafficking for both cells of the immune system and cancer cells during the process of metastasis. The ability to control new blood vessel growth but maintain immune surveillance would enhance our ability to tailor cellular recruitment into areas of inflammation and tumours growth. By dissecting the role of the endothelium and trafficking cells in these contexts, we expect to provide novel therapeutic targets.

Aims:

Our research aims to target the vasculature to control inflammation in asthma and skin disease, cancer metastasis and immune surveillance to provide novel targets for the treatment of disease utilising functional in vitro human models and nanobiotechnology.

Examples of work streams:

1) Development of novel flow systems for the determination of leukocyte endothelial interaction.
2) Utilising derivetised nanoparticles in the control of new vessel formation and cancer cell killing in relation to tumours and their metastasis.
3) Fundamental assessment of stress signalling in the endothelium and its control by small molecules inhibitors.
4) Development of in vitro models of cancer cell metastasis and recruitment.

Impacts and achievements:

Managing to integrate University wide collaborations in endothelial function and targeting which will grow in the coming months and years.

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

Dr Timothy Millar's photo

Publications

The University of Southampton's electronic library (e-prints)

Article

Millar, Timothy M. and Kanaras, Antonios G. (2013) Nanoparticulate drugs for the manipulation of angiogenesis. Therapeutic Delivery, 4, (10), 1217-1219. (doi:10.4155/tde.13.96).
Bartczak, Dorota, Muskens, Otto L., Sanchez-Elsner, Tilman, Kanaras, Antonios G. and Millar, Timothy M. (2013) Manipulation of in vitro angiogenesis using peptide-coated gold nanoparticles. ACS Nano, 7, (6), 5628-5636. (doi:10.1021/nn402111z ).
Bartczak, Dorota, Muskens, Otto L., Nitti, Simone, Millar, Timothy M. and Kanaras, Antonios G. (2012) Interactions of human endothelial cells with gold nanoparticles of different morphologies. Small, 8, (1), 122-130. (doi:10.1002/smll.201101422). (PMID:22102541).
Bartczak, Dorota, Nitti, Simone, Millar, T.M. and Kanaras, Antonios G. (2012) Exocytosis of peptide functionalized gold nanoparticles in endothelial cells. Nanoscale, 4, (15), 4470-4472. (doi:10.1039/C2NR31064C ).
Bartczak, Dorota, Muskens, Otto L., Millar, Timothy M., Sanchez-Elsner, Tilman and Kanaras, Antonios G. (2011) Laser-induced damage and recovery of plasmonically targeted human endothelial cells. Nano Letters, 11, (3), 1358-1363. (doi:10.1021/nl104528s). (PMID:21322611).
Bartczak, Dorota, Sanchez-Elsner, Tilman, Louafi, Fethi, Millar, Timothy M. and Kanaras, Antonios G. (2011) Receptor-mediated interactions between colloidal gold nanoparticles and human umbilical vein endothelial cells. Small, 7, (3), 388-94. (doi:10.1002/smll.201001816 ).
Grainge, C., Smith, A.J., Jugg, B.J., Fairhall, S.J., Mann, T., Perrott, R., Jenner, J., Millar, T.M. and Rice, P. (2010) Furosemide in the treatment of phosgene induced acute lung injury. Journal of the Royal Army Medical Corps, 156, (4), 245-250. (PMID:21275359).
Figura, M., Chilton, L., Liacini, A., Viskovic, M.M., Phan, V., Knight, D., Millar, T.M., Patel, K., Kubes, P., Giles, W.R., Tibbles, L.A. and Maric, M. (2009) Blockade of K(ATP) channels reduces endothelial hyperpolarization and leukocyte recruitment upon reperfusion after hypoxia. American Journal of Transplantation, 9, (4), 687-696. (doi:10.1111/j.1600-6143.2009.02553.x).
Millar, Timothy M., Phan, Van and Tibbles, Lee Anne (2007) ROS generation in endothelial hypoxia and reoxygenation stimulates MAP kinase signaling and kinase-dependent neutrophil recruitment. Free Radical Biology & Medicine, 42, (8), 1165-1175. (doi:10.1016/j.freeradbiomed.2007.01.015). (PMID:17382198).
Kanczler, Janos M., Millar, Timothy M., Bodamyali, Tulin, Blake, David R. and Stevens, Cliff R. (2003) Xanthine oxidase mediates cytokine-induced, but not hormone-induced bone resorption. Free Radical Research, 37, (2), 179-187. (doi:10.1080/1071576021000040673).
Millar, Timothy, Kanczler, Janos, Bodamyali, Tulin, Blake, David and Stevens, Cliff (2002) Xanthine oxidase is a peroxynitrite synthase: newlyidentified roles for a very old enzyme. Redox Report, 7, (2), 65-70. (doi:10.1179/135100002125000280). (PMID:12189051).
Stevens, C.R., Millar, T.M., Clinch , J.G., Kanczler, J.M., Bodamyali, T and Blake, D.R. (2000) Antibacterial properties of xanthine oxidase in human milk. Lancet, 356, (9232), 829-830. (doi:10.1016/S0140-6736(00)02660-X). (PMID:11022933).

Book Section

Bodamyali, Tulin, Kanczler, Janos M., Millar, Tim M., Stevens, Cliff R. and Blake , David R. (2003) Free radicals in rheumatoid arthritis: Mediators and modulators. In, Packer, Lester, Podda, Maurizio and Fuchs, Jürgen (eds.) Redox-Genome Interactions in Health and Disease. London, GB, Chemical Rubber Company Press, 591-611. (Oxidative Stress and Disease).
 

Research

Research Interests

Inflammation and regulatory T cell activation

Inflammation is a natural response to environmental stimuli but chronic inflammation can lead to compromised function. The body has a mechanism of controlling inflammation using regulatory T cells which help to return an inflammatory area back to normal physiology. In chronic inflammatory skin disease the role of the regulatory T cell and the interaction with the dermal endothelium is being studied as the mechanism of T cell activation via Programmed Death Receptor 1 (PD-1R) and its ligand requires an initial interaction with the vascular wall. This study will lead to potential new therapeutics to control T reg activity in the skin and other organs.

Funding: British Skin Foundation
Collaborators: Dr Chris Pickard, Prof Eugene Healy

Cancer cell recruitment, MAPKinase and endothelial activation

Inflammatory cells must interact with the vascular wall before transmigrating into the surrounding tissue. Cancer cells which have broken away from the primary tumour use similar mechanism during spread through the blood system so called haematogenous spread. We are detailing the interaction of breast cancer cells and the endothelium under flow conditions to mimic physiology and also in the presence of platelets as part of the recruitment process involves activation of the coagulation cascades. This study is using small molecule inhibitors to block endothelial activation and the interaction of platelets and cancer cells.

Nano particles and angiogenesis

New blood vessel formation (angiogenesis) is a required and carefully orchestrated event under normal physiological conditions. However, new blood vessel growth into tumours increases the risk of cancer spread. We are using novel nanotechnology to control angiogenesis in an attempt to reduce the spread of primary tumours. In collaboration with the Faculty of Astronomy and Physics, we are using gold nanoparticles to target endothelial cells directly, to block their ability to attach to basement matrix proteins and therefore prevent angiogenesis. We are also using tuned laser technology to target endothelial cells which contain gold nanoparticles in an attempt to ablate new blood vessel formation.

Funding: EPSRC
Collaborators: Dr Antonios Kanaras, Dr Tilman Sanchez-Eisner, Dr Otto Muskens, Dr Dorota Bartzak

Microfluidic devices and 3D models of extrasvasation

Modelling vascular parameters and devising microfluidic devices for use in biological research is an important method which will increase the complexity of invitro assays and reduce the requirement for animals in biological research. To this end we are developing microfluidic devices which mimic the vasculature and allow models of the lung or vascular beds to be formed. These devices use isolated human cells and sensors to measure important biological parameter such as permeability, oxygen and glucose. We are also developing in gel 3D vascular networks which will allow modelling of flow dynamics and provide an invitro assay of cancer intra and extravasation.

Funding: NC3Rs, FP7 (pending), AAIR
Collaborators: Dr Xunli Zhang, Dr Dyan Ankrett, MITHRA, Prof. Donna Davies, Prof Hywel Morgan

Academic unit:  Clinical and Experimental Sciences

Responsibilities

1. Postdoctoral supervision: Dr Dorota Bartzsak, 2010 -2011
2. PhD supervision: Dr James Hewinson, 2005
3. PhD supervision: Dr Emily Bennett,
4. MRes supervision: Dr Mark Masterson, 2005,
5. MRes supervision: Dr Maria Figura, 2006
6. Undergraduate research students: Mr Tim Keen 2010, Miss Laura Sweeney 2011, Yee Xuen Khoo 2011
7. Integrated PhD students - Miss Jo Underwood, Mr Alvaro Medina Barnuevo
8. Current PhD student: Miss Wen Chean Lim until Sept 2014

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

Teaching Responsibilities

1. Extensive teaching on the BM5 and BM4 undergraduate Medicine course including lectures, small group tutorials and practical sessions
2. Exam setting and marking of undergraduate and postgraduate (MSc) courses
3. Deputy course co-ordinator for the BM5 Gastrointestinal (GI) course
4. BM5 steering group committee member
5. Pharmacology lead for semester 3 BM5/4 course
6. Personal Tutor

Contact

Dr Timothy Millar
Faculty of Medicine
University of Southampton
Southampton General Hospital
Mailpoint 801
South Academic Block
Tremona Road
Southampton
SO16 6YD
or
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