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Dr Natalie Burrows

Research Interests

The Hypoxia-Inducible factors (HIF-1 and HIF-2) are transcription factors that mediate oxygen-sensing in cells. In the presence of oxygen, PHD enzymes hydroxylate HIF-α, enabling binding of von-Hippel-Lindau (VHL) protein leading to ubiquitylation and proteosomal degradation. Under low oxygen tensions (hypoxia), hydroxylation is reduced resulting in progressive HIF stabilisation and increased transcription of target genes. Mutations in VHL, PHD2 or HIF2A result in abnormal HIF activation in the presence of oxygen. HIF modulates genes involved in many physiological and pathophysiological processes including angiogenesis, glycolysis, differentiation, apoptosis and cell migration.

This pathway plays a crucial role in innate immunity and inflammation, having significant effects on macrophage behaviour, neutrophil apoptosis and increasing bactericidal activity of myeloid cells. Less is known about the role of HIF in adaptive immune responses. My work focuses on the role of the PHD-HIF-VHL pathway on B cell activation, apoptosis, differentiation and survival in mice and humans.

 

On-going projects in the Maxwell laboratory include: 

-          Assessing the role of the hypoxia pathway in mouse B cells: We have and are generating murine models with vhlh, Hif1α and Epas1 deleted from mouse B-lymphocytes.

-          We are examining the regulation and function of the HIF pathway in human EBV transformed lymphocytes.

-          As the hypoxia pathway is pharmacologically tractable there is capacity for this pathway to be manipulated for example to potentiate responses to vaccination or treat cancers, autoimmune diseases and transplant rejection. This will also be investigated.  

Key Publications

N Burrows, BA Telfer, G Brabant and KJ Williams. Inhibiting the phosphatidylinositide 3-kinase pathway blocks radiation-induced metastasis associated with Rho-GTPase and Hypoxia inducible factor-1 activity. Radiotherapy and Oncology (accepted 22/06/2013).

C Cawthorne, N Burrows, M Radigois, J Gregory, A Smigova, M Babur, I Wilson, A Danikas, KJ Williams. [18F]-FLT Positron Emission Tomography can be used to image the response of sensitive tumours to PI3-Kinase inhibition with the novel agent GDC-0941. Molecular Cancer Therapeutics 2013 May;12(5):819-28.

RG Gieling, M Babur, L Mamnani, N Burrows, BA Telfer, SR Williams, KE Davies, A Scozzafava, CT Supuran, KJ Williams. Anti-metastatic effect of the sulfonamide carbonic anhydrase IX inhibitor S4 in breast carcinoma xenografts. Journal of Medicinal Chemistry 2012 Jun 14;55 (11): 5591-600.

N Burrows, M Babur, J Resch, S Ridsdale, M Mejin, EJ Rowling, G Brabant and KJ Williams. GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 Kinase (PI3K) and Hypoxia inducible Factor-1α (HIF-1α) pathways. Journal of Clinical Endocrinology & Metabolism Dec 2011 96 (12): E1934–E1943.

N Burrows, M Babur, J Resch, KJ Williams and G Brabant. Hypoxia-inducible Factor (HIF) in thyroid carcinoma. Journal of Thyroid Research 2011; 762905.

N Burrows, J Resch, RL Cowen, R von Wasielewski, C. Hoang-Vu, CM West, KJ Williams and G Brabant. Expression of hypoxia-inducible factor 1α in thyroid carcinomas. Endocrine-related cancer 2010; 17:61–72.