Professor Tim Skerry BVet Med FRCVS Cert SAO PhD
Department of Oncology & Metabolism
F Floor, Medical School
Beech Hill Road
Telephone: +44 (0)114 215 9026
Professor of Orthopaedic Biology
- 2005 – Present: Professor of Orthopaedic Biology University of Sheffield;
- 2003 - 2005: Vice Principal Research RVC;
- 2001 – 2003: Head of Veterinary Basic Sciences; RVC
- 1995 – 2001: Professor of Cellular and Molecular Biology University of York;
- 1987 – 1995: Lecturer in Surgery, then Anatomy University of Bristol;
- 1984 – 1987: PhD Functional adaptation in bone;
- 1980 – 1986: Mixed practice, small animal practice, specialist orthopaedic practice;
- 1980: Veterinary Graduate RVC London.
After spending a considerable number of years researching the mechanisms behind the way that the skeleton responds to exercise, my interests have shifted substantially in recent years. Interest in the calcitonin family of hormones and receptors led to a project on understanding the roles of so-called receptor activity modifying proteins in bone (RAMPs). RAMPs are interesting accessory proteins that control the ligand selectivity of a small number of receptors. For example a calcitonin receptor (CTR) alone binds and responds primarily to the hormone calcitonin. However, co-expression of the CTR with any of the 3 human RAMPs leads to the heteromeric receptor complex becoming a one of 3 distinct receptors for the hormone amylin. Similarly, the calcitonin like-receptor (CLR) which is an orphan becomes a CGRP receptor with RAMP1 and either an adrenomedullin 1 or 2 receptor with RAMPs 2 and 3 respectively.
We have studied the roles of the RAMPs in bone by assessing the skeletal phenotypes of RAMP KO mice and shown that there appears to be no overt phenotype in RAMP 1 KO mice, there is a haploid insufficiency phenotype in RAMP2 heterozygotes with delayed development and intracortical porosity. In RAMP3 mice though there is accelerated development and an increased response of the bones to mechanical loading.
Our work on RAMPs has taken us into other directions too. Exploration of the role of RAMPs with other receptors where there is no change in ligand selectivity but a role in trafficking the receptors to the cell surface resulted in a paper on the need for RAMP1 for trafficking of the calcium sensing-receptor in a cell line not engineered to overexpress the proteins.
However, the main focus of the lab is now on development of small molecule antagonists of the AM2 adrenomedullin receptor. AM is involved centrally in regulation of blood pressure but it is also a potent player in tumorigenesis, where it has innate tumour cell to tumour cell actions, and roles in which AM released by the tumour upregulates AM2R expression in host cells around the tumour. As a broad spectrum AM antagonist would interfere with AM’s potent vasodilator effect, we cannot tractably use such an approach to block AM’s role in tumours. However, we have shown that the physiological roles of AM are maintained predominantly by the AM1 receptor (CLR+RAMP2) while the AM2 receptor (CLR+RAMP3) can be blocked without significant deleterious effects.
Our major research programme is now a Wellcome Trust funded drug discovery programme in which Dr Gareth Richards and I work with collaborators in Industry (Dr Karl Gibson, a modeller at Sandexis and Dr Matt Tozer formerly a medicinal chemist at Peakdale Molecular) and Professor Joe Harrity in the Department of Chemistry here in Sheffield to develop and optimise small molecule AM2R antagonists for cancer treatment.
External UK Research-Related Activities
- Member of MRC industrial studentships committee
Early life vitamin D depletion alters the postnatal response to skeletal loading in growing and mature bone. Borg SA, Buckley H, Owen R, Marin AC, Lu Y, Eyles D, Lacroix D, Reilly GC, Skerry TM, Bishop NJ. PLoS One. 2018 Jan 25;13(1):e0190675. doi:0.1371/journal.pone.0190675. eCollection 2018. PMID:29370213
Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.
Balasubramanian M, Hurst J, Brown S, Bishop NJ, Arundel P, DeVile C, Pollitt RC, Crooks L, Longman D, Caceres JF, Shackley F, Connolly S, Payne JH, Offiah AC, Hughes D; DDD Study, Parker MJ, Hide W, Skerry TM. Bone. 2017 Jan;94:65-74. doi: 10.1016/j.bone.2016.10.023. Epub 2016 Oct 24.PMID:27789416
Peak strain magnitudes and rates in the tibia exceed greatly those in the skull: An in vivo study in a human subject, Hillam RA, Goodship AE, Skerry TM, J Biomech. 2015 Sep 18;48(12):3292-8. doi: 10.1016/j.jbiomech.2015.06.021. Epub 2015 Jun 27, PMID: 26232812 [PubMed - indexed for MEDLINE] Free PMC Article
Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2), Weston C, Lu J, Li N, Barkan K, Richards GO, Roberts DJ, Skerry TM, Poyner D, Pardamwar M, Reynolds CA, Dowell SJ, Willars GB, Ladds G, J Biol Chem. 2015 Sep 18;290(38):23009-22. doi: 10.1074/jbc.M114.624601. Epub 2015 Jul 21, PMID: 26198634 [PubMed - indexed for MEDLINE] Free PMC Article
Inhibition of glutamate regulated calcium entry into leukemic megakaryoblasts reduces cell proliferation and supports differentiation, Kamal T, Green TN, Morel-Kopp MC, Ward CM, McGregor AL, McGlashan SR, Bohlander SK, Browett PJ, Teague L, During MJ, Skerry TM, Josefsson EC, Kalev-Zylinska ML, Cell Signal. 2015 Sep;27(9):1860-72. doi: 10.1016/j.cellsig.2015.05.004. Epub 2015 May 14, PMID: 25982509 [PubMed - indexed for MEDLINE]
Zinc-Induced Effects on Osteoclastogenesis Involves Activation of Hyperpolarization-Activated Cyclic Nucleotide Modulated Channels via Changes in Membrane Potential, Notomi T, Kuno M, Hiyama A, Ohura K, Noda M, Skerry TM, J Bone Miner Res. 2015 Sep;30(9):1618-26. doi: 10.1002/jbmr.2507. Epub 2015 May 31, PMID: 25762086 [PubMed - in process]
Role of receptor activity modifying protein 1 in function of the calcium sensing receptor in the human TT thyroid carcinoma cell line, Desai AJ, Roberts DJ, Richards GO, Skerry TM, PLoS One. 2014 Jan 13;9(1):e85237. doi: 10.1371/journal.pone.0085237. eCollection 2014.
The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading, Wang N, Rumney RM, Yang L, Robaye B, Boeynaems JM, Skerry TM, Gartland A. J Bone Miner Res. 2013 Jun;28(6):1446-56. doi: 10.1002/jbmr.1877. PMID: 23362109 [PubMed - indexed for MEDLINE] Free Article
Reduced bone turnover in mice lacking the P2Y13 receptor of ADP, Wang N, Robaye B, Agrawal A, Skerry TM, Boeynaems JM, Gartland A. Mol Endocrinol. 2012 Jan;26(1):142-52. doi: 10.1210/me.2011-1083. Epub 2011 Nov 22. PMID: 22108801 [PubMed - indexed for MEDLINE]
Haploinsufficiency of receptor activity-modifying protein-2 (RAMP2) causes reduced fertility, hyperprolactinemia, skeletal abnormalities, and endocrine dysfunction in mice, Kadmiel M, Fritz-Six K, Pacharne S, Richards GO, Li M, Skerry TM, Caron KM. Mol Endocrinol. 2011 Jul;25(7):1244-53. doi: 10.1210/me.2010-0400. Epub 2011 May 12. PMID: 21566080 [PubMed - indexed for MEDLINE] Free PMC Article
Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity, Whitehouse CA, Waters S, Marchbank K, Horner A, McGowan NW, Jovanovic JV, Xavier GM, Kashima TG, Cobourne MT, Richards GO, Sharpe PT, Skerry TM, Grigoriadis AE, Solomon E. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12913-8. doi: 10.1073/pnas.0913058107. Epub 2010 Jun 29. Erratum in: Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4428. PMID: 20616007 [PubMed - indexed for MEDLINE] Free PMC Article