Professor Andrew Silver, BSc, PhD, FHEA, FRCPath

 

Centre: Centre for Genomics and Child Health

 

MBBS: PBLs (Fundamental of medicine, metabolism, human development) and student selected components. Mentoring of first and second years.

Co-module lead, Human Genetic Disorders for second year BSc (Hons) Biomedical and medical genetics students

MSc in Gastroenterology: lecture, tutor and project supervision

Intercalated BSc in Experimental Pathology: project supervision

BSc(hons) Biomedical students: final year project supervision

 

Topics for PhD supervision:

Type 2 diabetes and epigenetic mechanisms in colorectal cancer

Understanding stenofibrosing disease in Crohn’s disease

Identifying novel epigenetic therapies for Crohn’s disease

Molecular genetics of colorectal cancer. Type 2 diabetes and epigenetic mechanisms in colorectal cancer. Understanding stenofibrosing disease in Crohn’s disease and identifying novel epigenetic therapies for Crohn’s disease. Role of DUOX2 in inflammatory bowel disease and cancer.

Recent and ongoing research projects:

A. Cancer

Type 2 diabetes (T2D) is increasing in prevalence and is a known risk for colorectal cancer (CRC). CRC patients with T2D have a poorer clinical outcome in terms of survival compared to non-diabetics. The consequences of hyperglycaemia at the cellular level remains largely unknown, but the consequences of environmental exposure to high glucose in the gut may include epigenetic forms of carcinogenic mutation. We are currently investigating findings linking dysregulated metabolism, elevated glycolysis and epigenetic modification of proteins in adenomas and CRC.

B. Inflammatory Bowel Disease.

Understanding stenofibrosing disease in Crohn’s disease and identifying novel epigenetic therapies. The cycles of chronic inflammation and repair associated with Crohn’s disease (CD) can result in tissue damage and scar tissue in the bowel wall, a process called fibrosis. This can cause a narrowing or stricturing of the bowel and blockage. A third of CD patients will develop strictures and experience symptoms of pain and vomiting as a consequence. The disease is progressive so understanding the causes is very important as current medical therapies cannot reverse or cure established fibrosis. Fibrotic strictures are the main reason for surgery in CD, which are associated with a high risk of unemployment and poor quality of life due to high recurrence rates. Intestinal fibrosis is a complex process. Our aim is to understand the mechanisms involved in CD fibrosis to enhance the prospects for new therapies. Currently, we are investigating chemical modification (acetylation) in histone proteins in fibroblasts from CD patients and are studying the modulation of histone acetylation, as a potential novel therapeutic treatment for CD fibrosis. Novel drug treatments would represent a significant clinical advance; both improving patients’ quality of life and reducing the cost of disease management.

Currently there are no biomarkers of intestinal fibrosis that might allow early identification and better management of patients at increased risk of stricture formation. Such biomarkers would also be useful for testing the efficacy of new drugs and provide useful insight into disease mechanisms. We have studied exported circulatory micro(mi)RNAs as potential biomarkers of structuring CD and have shown that circulating miRNAs have potential as non-invasive biomarkers of stricturing CD.

Role of DUOX2 in inflammatory bowel disease and cancer. Recently we have shown that the dual oxidase enzyme (DUOX) and its obligate maturation factor/partner encoded by (DUOXA) form the predominant hydrogen peroxide (H2O2)-producing enzyme system in human colorectal mucosa. The system releases significant amounts of H2O2 as part of the innate immune response. During bacterial infection and specifically during a ‘flare’ consistent with inflammatory bowel disease (IBD), the DUOX2/DUOXA2 system is upregulated significantly. H2O2 has significant capacity to killing pathogens and is needed to help in the recruitment of immune cells, mucosal healing and the resolution of inflammation. However, DUOX2 production of H2O2 might also contribute to DNA damage and mutation deep within damaged crypts increasing the risk of CRC in IBD patients. In collaboration with others, we have found that inhibition DUOX2 in pre-clinical models by chemotherapy may explain the reduced efficacy of certain drug combinations in clinical settings. This indicated that improved rationales for combining chemotherapeutic agents are necessary.

 

Research Group Members 

Amy Lewis, Research Fellow

Giulio Berti, Research Technician

 

Adam J, Ramracheya R, Chibalina MV, Hamilton A, Tarasov A, Zhang Q, Ternette N, Do HW, Rebelato E, Rorsman NJG, Martín-del-Río R, Lewis A, Özkan G, Spégel P, Saito K, Kato K, Igarashi K, Kessler BM, Pugh C, Tamarit-Rodriguez J, Mulder H, Clark A, Ashcroft FM, Frizzell N, Soga T, Silver A, Pollard PJ, Rorsman P. (2017) Fumarate hydratase deletion in pancreatic β-cells leads to progressive diabetes. Cell reports 20:3135-3148.

Nijhuis A, Thompson H, Adam J, Parker A, Gammon L, Lewis A, Bundy JG, Soga T, Jalaly A, Propper D, Jeffery R, Suraweera N, McDonald S, Thaha MA, Feakins R, Lowe R, Bishop CL, Silver A (2017). Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance. Hum Mol Genet. 26:1552-1564.

Urban BC, Collard TJ, Eagle CJ, Southern SL, Greenhough A, Hamdollah-Zadeh M, Ghosh A, Poulsom R, Paraskeva C, Silver A, Williams AC. (2016). BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling. Gut. 65:1151-64.

Santoro V, Jia R, Thompson H, Nijhuis A, Jeffery R, Kiakos K, Silver A, Hartley JA, Hochhauser D. (2015). Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer. J Natl Cancer Inst. Dec 30;108(6).

Rigoni A, Bongiovanni L, Burocchi A, Sangaletti S, Danelli L, Guarnotta C, Lewis A, Rizzo A, Silver A, Tripodo C, Colombo MP. (2015). Mast cells infiltrating inflamed or transformed gut alternatively sustain mucosal healing or tumor growth. Cancer Res. 75:3760-70.

Lewis A, Mehta S, Hanna LN, Rogalski LA, Jeffery R, Nijhuis A, Kumagai T, Biancheri P, Bundy JG, Bishop CL, Feakins R, Di Sabatino A, Lee JC, Lindsay JO, Silver A. (2015). Low serum levels of microRNA-19 are associated with a stricturing Crohn's disease phenotype. Inflamm Bowel Dis. 8:1926-34.

Felice C, Lewis A, Armuzzi A, Lindsay JO, Silver A. (2015). Selective histone deacetylase isoforms as potential therapeutic targets in inflammatory bowel diseases. Aliment Pharmacol Ther. 41:26-38.

Nijhuis A, Biancheri P, Lewis A, Bishop CL, Giuffrida P, Chan C, Feakins R, Poulsom R, Di Sabatino A, Roberto Corazza G, MacDonald TT, Lindsay JO, Silver A (2014). In Crohn’s disease fibrosis reduced expression of the miR-29 family enhances collagen expression in intestinal fibroblasts. Clinical Science 27:341-50.

View all Andrew Silver's Research Publications at: http://www.researchpublications.qmul.ac.uk