My research interest was triggered by my MSc project at the University of Southampton working with Professor ST Holgate and Dr AP Sampson on the molecular mechanisms of immune-inflammation. I was awarded a distinction for this project and offered a PhD position in the same lab. During my PhD I discovered that aspirin sensitive asthma is characterized by over-expression of leukotriene C4 synthase and the mechanisms underlying IL-5 activation of 5-lipoxygenase in eosinophils. My early and mid-postdoctoral training was undertaken in the lab of Professor Chilvers in the Department of Medicine at Cambridge, working on the biological and signalling mechanisms regulating neutrophil and eosinophil apoptosis In 2002, as part of the Chilvers lab, we reported on the oxygen sensing capacity of granulocytes and the essential role of the PHD/HIFα pathway in this response.
The above programme of work initiated my interest in oxygen sensing generally, and in particular the growing body of work exploring the differential effects of the two main isoforms of HIFα, namely HIF-1α and HIF-2α. I worked with Professor Randy Johnson between 2009-2016, initially at UCSD 2009-11, where I broadened my training in mouse genetics and phenotyping and was given the freedom to develop my own research interest, which led to the discovery of the unique and opposing effects of HIF-1/2α KO in the skin, whereby conditional KO of HIF-1α in the skin resulted in a 'hypertensive mouse' and HIF-2α KO a 'hypotensive mouse' (and accelerated wound healing), which was even resistant to the pressor effects of Ang-II infusion. The human relevance of these data was confirmed by finding reduced HIF-1α expression in skin biopsies of patients with mild hypertension compared to normotensive individuals. The appointment of Professor Johnson to a Wellcome Trust Principal Research Fellowship at PDN in Cambridge, plus my own move back to the UK allowed me to continue this work and establish new collaborations with Prof Nick Morrell (Dept Medicine) to explore further the physiological and pathological role of HIF-1α and HIF-2α in cardiovascular biology. I have now reported a series of important findings on pulmonary hypertension and vascular hypoxic responses. I found that blocking one aspect of HIF response via genetic deletion of HIF2 in the pulmonary vasculature completely blocked the onset of pulmonary hypertension in mice. I began my career as a group leader in Dept Medicine, University of Cambridge. There my lab undertook studies to determine whether small-molecule inhibitors (HIF2α antagonists-Peloton Therapeutics) that block this HIF pathway can offer therapeutic potential to modulate the initiation and progression of pulmonary hypertension.
We are interested in how the body/organ/cell responds/ acclimatises to low oxygen environments/hypoxia. This is relevant to a number of disease pathologies (including COPD, Pulmonary hypertension, asthma) but also to physiological homeostasis.
- Pulmonary hypertension is a progressive and destructive disease of the pulmonary vasculature. Currently there is no known cure, all current therapeutic intervention strategies only slow disease progression. Therefore, there is an unmet need for the development of new transformative therapies. We are currently working with Merck to investigate whether inhibition of HIF2-alpha represents a new therapeutic strategy to treat PAH patients.
- Inflammation, Granulocyte:Endothelial cell interaction. We are actively investigating how hypoxia/HIF modulates the communication process between granulocytes and endothelial cells. This is particularly relevant to chronic hypoxic lung disease including COPD and asthma.
Dr Andrew Murray (University of Cambridge)
Prof Randall Johnson (University of Cambridge)
Dr Laura Alexander-Crotty (University California San Diego)
Prof Nick Morrell (University of Cambridge)
Dr Amer Rana (University of Cambridge)
Dr Charlotte Summers (University of Cambridge)
Katharine Lodge (Academic Clinical Lecturer)
Danya Agha-Jaffer (Research Technician)
Macias D, Cowburn AS, Torres-Torrelo H, Ortega-Sáenz P, López-Barneo J, Johnson RS. HIF2-alpha is essential for carotid body development and function. Elife. 2018 Apr 19;7
Sim J, Cowburn AS, Palazon A, Madhu B, Tyrakis PA, Macías D, Bargiela DM, Pietsch S, Gralla M, Evans CE, Kittipassorn T, Chey YCJ, Branco CM, Rundqvist H, Peet DJ, Johnson RS. The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia. Cell Metab 2018 Apr 3;27(4)898-913
*Cowburn AS, Macias D, Summers C Chilvers ER, Johnson RS. Cardiovascular adaptation to hypoxia: the role of peripheral resistance. eLIFE Oct 2017, 16:6 e28755
Pocock, JM. Storisteanu, DML. Reeves, MB. Juss, JK. Wills, MR. Chilvers ER and Cowburn AS Human Cytomegalovirus Delays Neutrophil Apoptosis and Stimulates the Release of a Prosurvival Secretome. Frontiers in Immunology Sept 2017 25;8:1185
Thompson AAR, et al. Hypoxia determines survival outcomes of bacterial infection through HIF1a-dependent reprogramming of leukocyte metabolism. Science Immunology Feb 2017 10;2(8)
*Cowburn AS, Crosby A, Macias D, Branco C, Colaco R, Southwood M, Toshner M, Crotty-Alexander LE, Morrell NW, Chilvers ER, Johnson RS. A HIF2a-arginase axis is essential for the development of pulmonary hypertension. Proc Natl Acad Sci U S A 2016 Aug 2;113(31):8801-6
Semba H, Takeda N, Isagawa T, Sugiura Y, Honda K, Wake M, Miyazawa H, Yamaguchi Y, Miura M, Jenkins DM, Choi H, Kim JW, Asagiri M, Cowburn AS, Abe H, Soma K, Koyama K, Katoh M, Sayama K, Goda N, Johnson RS, Manabe I, Nagai R, Komuro I. HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nat Commun 2016 May 18;7:11635
Cowburn AS, Alexander LE, Southwood M, Nizet V, Chilvers ER, Johnson RS. Epidermal Deletion of HIF-2α Stimulates Wound Closure. J Invest Dermatol 2014 Mar;134(3):801-8
*Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling JC, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, Chilvers ER, Johnson RS. HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci U S A 2013 Oct 22;110(43):17570-5
Crotty Alexander LE, Akong-Moore K, Feldstein S, Johansson A, Nicatia S, Cowburn AS, Olson J, Cho JY, Isaacs H Jr, Johnson RS, Broide DH, Nizet V. Myeloid cell HIF-1α regulates asthma airway resistance and eosinophil function. J Mol Med 2013 May;91(5):637-44
*Cowburn AS, Summers C, Dunmore BJ, Farahi N, Hayhoe RP, Print CG, Cook SJ,Chilvers ER. Granulocyte/macrophage colony-stimulating factor causes a paradoxicalincrease in the BH3-only pro-apoptotic protein Bim in human neutrophils. Am J Respir Cell Mol Biol 2011 Jun;44(6):879-87
*Cowburn AS, Sobolewski A, Reed BJ, Deighton J, Murray J, Cadwallader KA, Bradley JR, Chilvers ER. Aminopeptidase N (CD13) regulates tumor necrosis factor-alphainduced apoptosis in human neutrophils. J Biol Chem 2006 May 5;281(18):12458-67
Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS,Johnson N, Chilvers ER. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 2005 Jan 3;201(1):105-15
*Cowburn AS, White JF, Deighton J, Walmsley SR, Chilvers ER. z-VAD-fmk augmentation of TNF alpha-stimulated neutrophil apoptosis is compound specific and does not involve the generation of reactive oxygen species. Blood2005 Apr 1;105(7):2970-2
*Cowburn AS, Cadwallader KA, Reed BJ, Farahi N, Chilvers ER. Role of PI3-kinasedependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival. Blood 2002 Oct 1;100(7):2607-16
*Cowburn AS, Holgate ST, Sampson AP. IL-5 increases expression of 5-lipoxygenaseactivating protein and translocates 5-lipoxygenase to the nucleus in human blood eosinophils. J Immunol 1999 Jul 1;163(1):456-65
*Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam BK, Penrose JF, Austen FK, Holgate ST, Sampson AP. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 1998 Feb 15;101(4):834-46
et al., 2021, Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension, European Respiratory Journal, Vol:57, ISSN:0903-1936
et al., 2021, Hypoxia-induced pulmonary hypertension - utilising experiments of nature, British Journal of Pharmacology, Vol:178, ISSN:0007-1188, Pages:121-131
et al., 2020, The impact of hypoxia on neutrophil degranulation and consequences for the host, International Journal of Molecular Sciences, Vol:21, ISSN:1422-0067, Pages:1-21
et al., 2019, Neutrophil GM-CSF receptor dynamics in acute lung injury, Journal of Leukocyte Biology, Vol:105, ISSN:0741-5400, Pages:1183-1194
et al., 2018, Correction: HIF-2α is essential for carotid body development and function., Elife, Vol:7