Faculty of Medical Sciences

Staff Profile

Dr Sally Coulthard

Senior Research Associate

Background

Background

Research associate at Newcastle University since October 1988, PhD awarded in December 2000 and a senior research associate since January 2002

Roles and Responsibilities

Research Associate Representative and Chair person (2002-2007)
Safety committee member, deputy ACGM officer (1999-2000), (2004-2009)

Qualifications

PhD, Newcastle University (2000)
Fellowship of the Institute of Medical Laboratory Scientific Officers, Newcastle Polytechnic (1988)
BSc (Hons) Botany and Zoology, Leeds University (1983)

Previous Positions

Research Associate 2, Newcastle University (Jan 2002 - present)
Research Associate 1A, Newcastle University (Sept 1997 - Dec 2001)
Junior Research Associate 1B, Newcastle University (Oct 1991 - Aug 1997)

Memberships

Member of European Association for Cancer Research

UK Purine Club 

Honours and Awards

AACR-AFLAC Young Investigator Award at the AACR 1999 Special Conference, Molecular Determinants of Sensitivity to Antitumour Agents, Whistler, Canada, February 1999
Young Investigator Award at the European Organisation for Research and Treatment of Cancer, Nancy, France, January 21-24th 1998

Informal Interests

Keeping fit

Research

Research Interests

6-Mercaptopurine, 6-thioguanine and azathioprine metabolism in inflammatory bowel disease, immunosuppression and leukaemia

Other Expertise

The laboratory techniques involved in my projects broadly encompass cell culture, (including drug sensitivity, transfection and transduction of specific genes); molecular biological techniques (DNA/RNA isolation, cloning, PCR, Real-time PCR, TaqMan assays, DNA sequencing, mutation screening); HPLC (enzyme activity analysis, incorporated thioguanine nucleotides into DNA, thiopurine metabolite levels); LC-MS/MS for thiopurine metabolite levels and protein expression analysis (western blotting), computational techniques involve the use of COPASI and CellDesigner.

Current Position

I have a part-time temporary position with Prof Ann Daly that entails the management and maintenance of a clinical database, DNA extraction and preparation of DNA for Genome wide association studies (GWAS). I am also determining the thiopurine methyltransferase status in those patients that have developed drug induced liver toxicity to thiopurines (azathioprine and 6-mercaptopurine) to compliment the GWAS studies.

Current Research

My current research interest is based on the premise that using drugs designed to interfere with purine metabolism and DNA/RNA synthesis e.g. the thiopurines; azathioprine, 6-thioguanine and 6-mercaptopurine, it is possible to disturb the purine balance in cells such that the contribution of specific enzymes and pathways can be interrogated. For example the thiopurines are metabolised to thioguanine nucleotides that can be incorporated into DNA and RNA (both nuclear and mitochondrial) as fraudulent bases thus triggering cellular responses such as DNA repair, apoptosis and/or autophagy. In addition these drugs also inhibit de novo purine synthesis directly thus allowing the contribution of salvage of purines on cell survival and cell mobility to be determined.

To investigate such effects I have been using two approaches: an in vivo laboratory approach and a computational approach. In the laboratory I have been using the thiopurines in drug sensitivity assays, either alone or in combination with other drugs that interfere with purine synthesis in the cell and measuring thiopurine metabolites, expression of genes involved in autophagy (in collaboration with Linköping University) and apoptosis and cell motility. I also managed a project as PI that determined the contribution of mitochondria to thiopurine sensitivity by measurement of drug response and thioguanine incorporation in nuclear and mitochondrial DNA using cell lines that are mitochondrial DNA-compromised compared to their parental counterpart in collaboration with Prof Mark Birch-Machin (ICM) and Dr Redfern (NICR). The computational approach is in collaboration with Drs. Redfern and Shanley (IAH). With a joint PhD student, we are developing a model of thiopurine metabolism using CoPaSi (open source dynamic-modelling software) based on a published purine model using data generated in our laboratory and data from the literature to investigate how pathways of DNA damage and nucleotide synthesis interact to determine cellular outcome in terms of cell death, senescence, or repair and survival.

Future Research Plans

These projects underpin my future research plans. I have recently applied for funding from The Broad Foundation (award pending) to improve treatment patients suffering from inflammatory bowel disease with azathioprine, either alone or in combination with allopurinol and substantially reduce the chances of non-response side effects by understanding the underlying mechanisms of action of thiopurines to improve patient targeting. Essentially, this pilot project will use a technique developed to measure thiopurine metabolites in white blood cells (co-funded by the JRO Newcastle Healthcare Charity) and correlate this to red cell metabolites and gene expression changes from patient samples pre- and on thiopurine treatment.

Grants awarded

1.       Allan J, Coulthard SA, Redfern CPF. Targeted therapy for chronic myeloid leukaemia in blast crisis. Tyneside Leukaemia Research Fund £56,458 to start July 1st 2012 until September 30th 2013

2.       Redfern CPF, Coulthard SA and Berry P. Development of LC-MS/MS assay for thiopurine metabolite measurement: submitted to Joint Research Executive committee, Newcastle Healthcare Charity (RVI/NGH) and Newcastle Upon Tyne hospitals NHS Charity for £40,212 for 6-months funding starting January 1st 2012

3.       Coulthard SA, Redfern CPF; Birch-Machin M; Swalwell H.: Role of mitochondrial DNA damage in thiopurine toxicity JGW Patterson Foundation (£48,000) April 2011-March 2012

4.       Redfern CPF; Shanley DP; Coulthard SA:  Computational modelling of the interactions between pathways of DNA damage and nucleotide synthesis. BBSRC DTG PhD studentship in the area “Systems approach to biological research” (£70,000) October 2010-September 2013

5.       Redfern CPF, Coulthard SA, Plummer ER and Calvert H. Expanding the therapeutic range of thiopurine drugs. Cancer Research UK (£142,412) January 2009-September 2010

6.       Curtin N.J., Plummer E.R Coulthard SA Poly (ADP-ribose) polymerase pharmacogenetics and pharmacoproteomics in patients receiving anticancer therapy (£89,009.50) American Institute for Cancer Research 1st October 2006-30th September 2009

7.       Hogarth LA, Coulthard SA, Hall AG. The Role of p21 CIP/WAF/SD11 inactivation in acute lymphoblastic leukaemia Tyneside Leukaemia Research Fund (£20,000.00) 1st October 2004-30th September 2006 

8.       Coulthard SA, Leslie M, and Hall AG. Transcriptional regulation of asparagine synthetase expression (£75,540) Tyneside Leukaemia Research Fund, 1st October 2004-30th September 2007.

9.       Hogarth LA, Coulthard SA, Hall AG. The Role of p21 CIP/WAF/SD11 inactivation in acute lymphoblastic leukaemia Newcastle Healthcare Charity (£9,000.00) 1st February 2004-31st January 2005

10.   Hogarth LA, Coulthard SA, Hall AG. The Role of p21 CIP/WAF/SD11 inactivation in acute lymphoblastic leukaemia (£45,231) Tyneside Leukaemia Research Fund, 1st October 2003-30th September 2006.

11.   Boddy, AV, Coulthard SA, Hogarth LA. Pharmacological Studies in support of clinical trials with MG98 British Biotech Parmaceuticals Ltd.(£27,623) 1st October 2003-31st December 2005

12.   Coulthard SA, Hall AG. Lometrexol-Selective treatment for relapsed childhood Leukaemia? (£53,670) Tyneside Leukaemia Research Fund, 1st October 2002-30th September 2005.

13.   Hall AG, Coulthard SA, Hogarth LA, Irving JAE. Optimisation of Chemotherapy in Childhood Acute Lymphoblastic Leukaemia. (£1,967,563): Leukaemia Research Fund, 1st April 2002- 31st March 2007.

14.   Hall AG, Hogarth LA, Coulthard SA., Pearson, A.D.J., The Role of Thiopurine Methyltransferase in determining Sensitivity to Thiopurine Drugs (£49,724): Leukaemia Research Fund (Clinical Training Fellowship) 1st June 2001 – 31st May 2002.

15.   Hall AG, Case MC and Coulthard SA. A Study of the cytotoxic effect of Buthionine Sulphoxide in neuroblastoma (£70,869): North of England Children’s Cancer Research Fund.1st July 1998 –30th June 2000.

Teaching

Undergraduate Teaching

I give lectures and seminars to BSc students on the Advanced Pharmacogenetics module (PED3005) and supervise students on the undergraduate BSc projects module CMB3000.

Postgraduate Teaching

I give lectures and seminars on the Medical and Molecular Biosciences MRes Systems Biology module (MMB8023). 

I have supervised 7 PhD students as detailed below:

 

1.   Sarah McGarrity (PhD student), co-supervisor “Computation modelling of the interactions between pathways of DNA damage and nucleotide synthesis” BBSRC, 1st October 2010-30th September 2013

2.   Tomasz Zaremba (PhD student), co-supervisor “Poly (ADP-ribose) polymerase pharmacogenetics and pharmacoproteomics in patients receiving anticancer therapy” AICR 1st October 2006- 30th September 2009

3.   Sotiris Georgantopoulos (PhD student), principal supervisor: “Transcriptional regulation of asparagine synthetase expression”. Tyneside Leukaemia Research Fund, 1st October 2004-30th September 2007

4.   Nadia Thornton (PhD student), principle supervisor: “Lometrexol-Selective treatment for relapsed childhood leukaemia?” Tyneside Leukaemia Research Fund October 2002- September 2005.

5.   Mark Leslie, (PhD student) principle supervisor: “The Molecular Basis of Resistance to L-asparaginase in vivo” Leukaemia Research Fund, Gordon Pillar Studentship October 2000-September 2003.

6.   Lisa Bloodworth, (PhD student) co-supervisor: “Mechanisms of drug resistance in mismatch repair deficient cells” Tyneside Leukaemia Research Fund October 2000-September 2003.

7.   Dr Margaret Little, (Clinical Training Fellowship; PhD) co-supervisor: “The Role of Thiopurine Methyltransferase in determining Sensitivity to Thiopurine Drugs” October 1998-May 2002. Funded by the Leukaemia Research Fund.

 

Publications