Rachel Knott

Dr Rachel Knott

Email: r.knott@rgu.ac.uk
Tel: +44 (0) 1224 262524
Location: PC12, SH

Position: Reader

Key duties and responsibilities

As Graduate School Leader I am responsible for the research students within the Institute of Health & Welfare Research with respect to their management, training and for the strategic development of our research student population. I am Course Leader for the Doctorate in Professional Practice course which is now open to receive applications for October 2011.

I am also a member of the Course Management Team for the Postgraduate Certificate in Research Methods, and teach both undergraduate and postgraduate students in the area of research methods, molecular and cell biology, biotherapy, pharmacogenomics and pharmacogenetics.

I am actively involved in research in the vascular complications of diabetes, oral insulin delivery and Cystinosis. In addition, I am a Professional member of Diabetes UK and the Biochemical Society and a Fellow of the Higher Education Academy.

Academic background

Following completion of my BSc in Biological Sciences at the University of Plymouth I studied at Reading University for an MSc in Virology. I then moved to Aberdeen where I carried out my PhD studies and graduated in 1988 from the University of Aberdeen. I joined the Robert Gordon University in 1999 following Research Fellowships at The Rowett Research Institute and the University of Aberdeen.

Current research interests

The incidence of diabetes has increased significantly in recent years. In 1985 there was an estimated 30 million people with diabetes and this number increased to 135 million in 1995 and 177 million in the year 2000. With this increase there is a concomitant rise in the national health care costs for the management of the diabetes itself and for the variety of complications that arise from this disease.
My work seeks to identify the mechanism of vascular damage resulting from the prevailing high concentrations of glucose and to evaluate the efficacy of various therapeutic intervention strategies using a variety of cellular and molecular tools.

1. Glucose-mediated regulation of gene expression.

Glucose enters the endothelial cell via integral membrane proteins called glucose transporters. The sensitivity of a tissue to hyperglycaemia is therefore closely associated with the potential susceptibility of the tissue to the characteristically high glucose concentrations of a patient with diabetes. In addition to the ability of glucose to regulate the expression of the transporters themselves, elevated intracellular concentrations of glucose and/or the intermediate metabolites of glucose are known to be involved with the stability of mRNAs and proteins. Specific knock-out of a gene and/or gene product can greatly facilitate our understanding of that gene in the disease process.

2. Nutrient mediated changes in intracellular communication and retinal endothelial cell response.
High glucose concentrations may affect cell responsiveness. This has been demonstrated using cultured retinal endothelial cells exposed to elevated concentrations of glucose (20mmol/l) in the presence of insulin like growth factor type 1 (IGF1). Normally, we would expect to see a peak in the level of p42/44 after 15 minutes in the presence of 1GF-1. In high glucose concentrations this was no longer evident.

Figure 2: Time course of MAPK activation following IGF1 treatment. Cells incubated in high glucose concentration did not show increased activation of p42/44 MAPK. (McBain, Robertson, Muckersie, Forrester and Knott, Metabolism, Clinical and Experimental, 52, p547 - 551 2004).

3. Relationship between oxidative stress, cell damage and functional changes in endothelial cells.

Oxidative stress induced by high glucose concentrations and/or low oxygen is known to be a significant factor in the onset of the clinical signs of the vascular complications of diabetes. Using multiple approaches to investigate therapeutic intervention at the basic science level and extending this to the clinic it is possible to investigate the mechanism of vascular disease.

A) Control B) 20mM glucose

Figure 3. Comet assay demonstrating that high glucose concentrations increases DNA damage in an endothelial cell line.

Project titles

The role of glucose concentration in the regulation of the expression of hypoxia inducible factor type 1 alpha (HIF1-a) - Investigation of the efficacy of topical application of hypoglycaemic agents and antioxidants to facilitate wound healing in diabetic patients.
Investigation of the efficacy of topical application of hypoglycaemic agents and antioxidants to facilitate wound healing in diabetic patients.
Mechanism of hyperglycaemia induced dysfunction of intracellular signalling in response to insulin like growth factor type 1

Publications

Omran Z, Kay G, Hector EE, Knott RM, Cairns D. (2011) Folate pro-drug of cystamine as an enhanced treatment for nephropathic cystinosis. Bioorg Med Chem Lett. 15;21(8):2502-4.

Omran Z, Kay G, Di Salvo A, Knott RM, Cairns D. (2011) PEGylated derivatives of cystamine as enhanced treatments for nephropathic cystinosis. Bioorg Med Chem Lett. 2011 Jan 1;21(1):45-7.

Omran Z, Moloney KA, Benylles A, Kay G, Knott RM, Cairns D (2011) Synthesis and in vitro evaluation of novel pro-drugs for the treatment of nephropathic cystinosis. Bioorg Med Chem. 2011 Jun 1;19(11):3492-6. Epub 2011 Apr 16.

Thompson C, Cheng WP, Gadad P, Skene K, Smith M, Smith G, McKinnon A, Knott R. Uptake and Transport of Novel Amphiphilic Polyelectrolyte-Insulin Nanocomplexes by Caco-2 Cells-Towards Oral Insulin. (2011) Pharm Res. 28(4):886-96.

B McCaughan, Kay, G, Knott RM and Cairns D, (2008) A Potential new prodrug for the Treatment of Cystinosis: Design, Synthesis and In vitro determination Bioorg. Med. Chem. Lett. 2008, 18 (5), 1716-1719.

RM Knott,Hector E, Moir D (2006) High Glucose concentration enhances the stability of HIF1 alpha mRNA in human endothelial cells. International Diabetes federation Blackwell Publisher. Oxford.

MacKinnon J, Knott RM, Forrester JV (2004) Lymphocytes in diabetic retinopathy: evidence of altered L-selectin expression in lymphocytes and increased adhesion to endothelium in patients with diabetic retinopathy. British Journal of Ophthalmology. 88, 1137-1141.

McBain VA, Robertson M, Muckersie, E, Forrester, and R M Knott (2003) High glucose concentration decreases insulin-like growth factor type-1 mediated mitogen activated protein kinase C activation in bovine retinal endothelial cells. Metabolism, Clinical and Experimental, 52(5), 547-551.

R M Knott, E Hector, M Cotter, N E Cameron, I Fordyce, S Ferguson and D Moir (2003). Alpha lipoic acid reduces expression of hypoxia inducible factor type 1 alpha in the sciatic nerve of streptozotocin induced diabetic rats. Diabetologia A401, 117.
RM Knott, and JV Forrester (2003) Pathogenesis of diabetic retinopathy and cataract Chapter 48 In, Textbook of Diabetes Eds. Pickup and Williams. Blackwell Press.

RM Knott, E Hector, V Zampoulis, M Cotter, NE Cameron, I Fordyce and L Steel (2002) Diabetes Induced expression of hypoxia inducible factor type 1 alpha. Diabetic Medicine 19 (2), p234.
S. Wileman, RM Knott, B. Redmill, J. V. Forrester, and N. A. Booth. (2000) TGF-beta mediated regulation of PAI-1 activity in human retinal endothelial cells. British Journal of Ophthalmology. 84:417-422.

RM Knott and McBain V (2000) Mechanism of glucose mediated dysfunction of endothelial cell growth: implications for wound healing. Journal of Pharmacy and Pharmacology 52. 1.
S. Wileman, RM Knott, B. Redmill, J. V. Forrester, and N. A. Booth. (2000) TGF-beta mediated regulation of PAI-1 activity in human retinal endothelial cells. British Journal of Ophthalmology. 84:417-422.

RM Knott, M. Robertson, E. Muckersie, V. Folefac, F. Fairhurst, S. Wileman, and J. V. Forrester. (1999) A model system for the study of human retinal angiogenesis: activation of monocytes and endothelial cells and the association with the expression of the monocarboxylate transporter type 1 (MCT-1).European Journal of Diabetes, Diabetologia 42:870-877.

RM Knott, M. M. Pascal, C. Ferguson, J. Leiper, J. A. Olson, E. Muckersie, M. Robertson, and J. V. Forrester. (1999) Regulation of transforming growth ), basic fibroblast growth factor (bFGF) and vascularfactor-beta (TGF- endothelial cell growth factor (VEGF) messenger RNA in peripheral blood leucocytes in patients with diabetic retinopathy. Metabolism: Clinical & Experimental 48 (9):1-8.

RM Knott, M. Robertson, E. Muckersie, V. Folefac, F. Fairhurst, S. Wileman, and J. V. Forrester. (1999) A model system for the study of human retinal angiogenesis: activation of monocytes and endothelial cells and the association with the expression of the monocarboxylate transporter type 1 (MCT-1). European Journal of Diabetes, Diabetologia 42:870-877.

M. Pascal, J. V. Forrester, and RM Knott. (1999) Glucose mediated regulation of transforming growth factor-beta and TGF-beta receptors in human retinal endothelial cells. Current Eye Research 19 (2):162-170.