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Mark Gurnell

University Lecturer (Clinical)

Department of Medicine

mg299@mole.bio.cam.ac.uk

 

Research Interests

Staff photo1. Nuclear receptors in human disease
Support:
Wellcome Trust Programme Grant (with Professor VKK Chatterjee)
Programme Aims:
Many commonly prescribed drugs act via nuclear receptors and our research investigates their role in human disease. Resistance to Thyroid Hormone (RTH) is a genetic disorder with variable tissue refractoriness to thyroid hormone action and we have collected the largest number of RTH families worldwide with thyroid hormone receptor (TR) beta gene defects. We have also identified the most cases with peroxisome proliferator-activated receptor gamma (PPARgamma) gene defects and severe insulin resistance. Current research interests include: identification of novel genetic disorders of TR or PPARgamma action; the study of subjects with abnormal receptor function to better understand the basis of their disorder; the investigation of defective nuclear receptor function in cells/tissues from affected individuals.

2. Acromegalic Cardiovascular & Respiratory Outcomes with Primary somatostatin Analogue Therapy (‘ACROPAT’ trial)
Support:
Ipsen Fund Project Grant
Trial Aims:
Untreated acromegaly is associated with major cardiovascular and respiratory sequelae. Although pituitary surgery, the current mainstay of treatment, reduces tumour bulk and growth hormone hypersecretion, it is non-curative in 40-50% of cases and may result in more global hypopituitarism even when undertaken by an experienced neurosurgeon. The ‘ACROPAT’ trial addresses two important questions: (i) does primary medical therapy with the long-acting somatostatin analogue Lanreotide Autogel improve surgical outcome? (ii) Is there a subgroup of acromegalics who could safely be treated with primary medical therapy alone? To answer these questions, newly diagnosed patients are currently undergoing detailed endocrine, respiratory (Dr J Shneerson, RSSC Papworth Hospital), cardiovascular (Dr I Wilkinson, Clinical Pharmacology, ACCI; Dr D Dutka, Cardiovascular Medicine, ACCI) and radiological (Dr N Antoun, Neuroradiology, Addenbrooke’s) profiling, both before and after 6 months of primary medical therapy, and then at 9-12 months post-surgery.

Our research is funded by the Wellcome Trust and the Ipsen Fund.

 

Selected Publications

 

Szatmari I, Töröcsik D, Agostini M, Nagy T, Gurnell M, Barta E, Chatterjee K, Nagy L. PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood. 2007 Nov 1;110(9):3271-80. Epub 2007 Jul 30. Abstract

 

Mackenzie IS, Gurnell M, Balan KK, Simpson H, Chatterjee K, Brown MJ. The use of 18-fluoro-dihydroxyphenylalanine and 18-fluorodeoxyglucose positron emission tomography scanning in the assessment of metaiodobenzylguanidine-negative phaeochromocytoma. Eur J Endocrinol. 2007 Oct;157(4):533-7. Abstract

 

Gurnell M. 'Striking the Right Balance' in Targeting PPARgamma in the Metabolic Syndrome: Novel Insights from Human Genetic Studies. PPAR Res. 2007;2007:83593. Abstract

 

Agostini M, Schoenmakers E, Mitchell CS, Szatmari I, Savage DB, Smith AG, Rajanayagam O, Semple RK, Luan J, Bath L, Zalin AN, Labib M, Kumar S, Simpson H, Blom D, Marais AD, Schwabe JWR, Barroso I, Trembath R, Wareham NJ, Nagy L, Gurnell M, O’Rahilly S, & Chatterjee VKK. 2006. Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance. Cell Metabolism, 4(4):303-311. Abstract

 

Gurnell M. 2005. Peroxisome proliferator-activated receptor gamma and the regulation of adipocyte function: lessons from human genetic studies. Best Pract Res Clin Endocrinol Metab, 19(4):501-23. Abstract

 

Semple RK, Meirhaeghe A, Vidal-Puig AJ, Schwabe JWR, Wiggins D, Gibbons GF, Gurnell M, Chatterjee VKK, O’Rahilly S. 2005. A dominant negative human peroxisome proliferator-activated receptor (PPAR){alpha} is a constitutive transcriptional corepressor and inhibits signaling through all PPAR isoforms. Endocrinology, 146(4):1871-82. Abstract

 

Agostini M*, Gurnell M*, Savage DB, Wood EM, Smith AG, Rajanayagam O, Games KT, Levinson SH, Xu HE, Schwabe JWR, Willson TM, O’Rahilly S, Chatterjee VKK. 2004. Tyrosine agonists reverse the molecular defects associated with dominant negative mutations in human peroxisome proliferator-activated receptor gamma. Endocrinology, 145(4):1527-1538. (*joint first authors) Abstract

 

Gurnell M. 2003. PPARg and metabolism – insights from the study of human genetic variants. Clinical Endocrinology, 59(3):267-77. Abstract

 

Gurnell M*, Savage DB*, Chatterjee VKK & O’Rahilly. S 2003. The Metabolic Syndrome: Peroxisome Proliferator-Activated Receptor gamma and Its Therapeutic Modulation. Journal of Clinical Endocrinology & Metabolism, 88(6):2412-2421. Abstract

 

Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams RL, Umpleby AM, Thomas EL, Bell JD, Dixon AK, Dunne F, Boiani R, Cinti S, Vidal-Puig A, Karpe F, Chatterjee VK, O'Rahilly S. 2003. Human Metabolic Syndrome Resulting From Dominant-Negative Mutations in the Nuclear Receptor Peroxisome Proliferator-Activated Receptor-gamma. Diabetes, 52:910-917. Abstract

 

Savage DB*, Agostini M*, Barroso I*, Gurnell M*, Luan JA*, Meirhaeghe A, Harding A-H, Ihrke G, Soos MA, Rajanayagam O, George S, Berger D, Thomas EL, Bell JD, McCarthy M, Hattersley AT, Hitman GA, Levy J, Walker M, Meeran K, Ross R, Vidal-Puig A, Wareham NJ, O’Rahilly S, Chatterjee VKK, Schafer AJ. 2002. Digenic inheritance of severe insulin resistance in a human pedigree. Nature Genetics, 31(4):379-384. (*joint first authors) Abstract


Gurnell M*, Wentworth JM*, Agostini M, Adams M, Collingwood TNC, Provenzano C, Browne PO, Rajanayagam O, Burris TP, Schwabe JW, Lazar MA and Chatterjee VKK. 2000. A dominant negative PPARg mutant is a constitutive repressor in vitro and inhibits PPARg action in vivo. Journal of Biological Chemistry, 275:5754-5759. (*joint first authors) Abstract

 

Barroso I*, Gurnell M*, Crowley VEF*, Agostini M, Schwabe JW, Soos MA, Maslen GLl, Williams TDM, Lewis H, Schafer AJ, Chatterjee VKK & O’Rahilly S. 1999. Dominant negative mutations in human PPARg are associated with severe insulin resistance, diabetes mellitus and hypertension. Nature, 402:880-883. Abstract