Dr Tom Van Agtmael

Reader (Institute of Cardiovascular & Medical Sciences)
Associate (Institute of Molecular Cell & Systems Biology)
Associate (School of Life Sciences)

telephone: 01413306200
email: Tom.VanAgtmael@glasgow.ac.uk

R423 Level 4, Institute of C&MS, Davidson Building, Glasgow G12 8QQ

ORCID iD https://orcid.org/0000-0003-4282-449X

Biography

Following his undergraduate training in Biochemistry at the University of Antwerp (Belgium), Dr. Van Agtmael obtained his PhD in molecular genetics at the Murdoch Childrens Research Institute in Melbourne (Australia). He then moved to the MRC Human Genetics Unit in Edinburgh for his post-doctoral training as an EU Marie Curie Fellow during which he identified the first vertebrate Col4a1 mutations and implicated type IV collagen in eye and kidney disease. Following a CVRI Wellcome Trust Fellowship at the University of Edinburgh, he was awarded a MRC New Investigator Research Grant to investigate the role of collagen IV in vascular biology. He then joined the University of Glasgow as a RCUK Fellow in Human Molecular Genetics where he established his research group within the Institute of Cardiovascular and Medical Sciences.

Research interests

Investigating the role of the extracellular matrix in vascular, eye and kidney disease to uncover new therapies.

Without an extracellular matrix, there would only be single cells and life is not possible. Our understanding of the roles of the extracellular matrix in disease and human health has gone from a simple structural support to a biological active structure that plays a key role in all aspects of cell and tissue function. Collagen is the major component of the extracellular matrix and of the human body. Mutations and defects in collagen and the extracellular matrix (ECM) cause complex genetic diseases that affect multiple tissues for which often there are no treatments. Moreover the ECM plays an important role in many common disorders such as vascular and cardiac disease, fibrosis, cancer, and degenerative age related diseases. However, the mechanisms by which this occurs remains unclear and this poor understanding forms a barrier to much needed treatments.

Our research aims to address this by investigating how mutations in collagen proteins cause disease with the aim of developing highly effective treatments. For this we use a large number of different approaches to analyse the mutations and disease from the molecular to patient level. Please see below for some of the ongoing projects within the lab. If you are interested in joining us, please do get in touch as we are keen to explore new avenues.

Collagen IV, basement membranes and cerebrovascular, eye and kidney disease.

Vascular and cerebrovascular disease are major causes of death and disability that place a significant burden on Societies and healthcare systems worldwide. The analysis of rare genetic forms of these diseases will help our understanding of the common forms of these disorders, and treatment development. Through the analysis of mouse models, we identified for the first time that mutations in the genes COL4A1 and COL4A2 (collagen IV alpha chain 1/2) cause eye and kidney disease together with stroke and cerebrovascular defects (Van Agtmael et al 2005, 2010, Plaisier et al 2007). This complex syndrome, referred to as COL4A1 related syndrome, also includes HANAC and PADMAL syndrome which we helped to describe (Plaisier et al 2007, Verdura et al 2016). COL4A1 related diseases remains poorly defined and current projects are ongoing within the lab to help define the disease to help the patients and clinicians with managing the disease and provide better disease prognosis.

Importantly, we also established that collagen IV is a risk factor for haemorrhagic stroke in the general population and acts through both rare and common variants (collaborations with Prof. Anderson and Rosand (Harvard University) and Al Shahi Salman (Edinburgh)(Chung et al 2021, Rannikmae et al 2015). Combined with data from other Mendelian forms of cerebrovascular disease, this has highlighted the extracellular matrix as a potential convergent critical component of the disease mechanism of cerebrovascular disease. Image of a figure

A major focus is to uncover how these genetic variants and mutations cause disease. We uncovered they act via defects in the extracellular matrix but they also affect intracellular pathways such as endoplasmic reticulum stress (Jones et al 2019, Murray et al 2014, Van Agtmael et al 2010, Van Agtmael et al 2005). Moreover, we identified they may have tissue and/or cell specific mechanisms providing further complexity in how they cause disease (Jones et al 2016). Yet the relative contribution of these mechanisms and how they result in the different pathologies is entirely unclear and represent a major gap in our knowledge. As a result, to develop effective and safe treatments it is necessary to understand the disease mechanisms at the molecular level and identify pathways and molecules that can alter disease development. Our recent work using biomaterials suggested a role for fibronectin and integrin in this aspect (collaboration Prof. Manuel Salmeron-Sanchez, Centre for the Cellular Microenvironment, Glasgow)(Ngandu Mpoyi et al 2020). Several projects are available to determine disease mechanisms, employing cell culture and animal models coupled with a battery of approaches ranging from electron and atomic force microscopy to genetics, biochemistry and physiology (collaboration Prof. Delles, Smith, Loughrey, Fuller in CAMS). These mechanisms will then be targeted with the aim of modulating disease. For example, targeting ER stress via PBA was able to prevent and reduce stoke severity in mice, but was unable to modulate the eye and kidney defects (Jones et al 2019). These approaches provide a powerful stepping stone to achieve our long-term aim of addressing the basis of disease from gene to patient level and inform on novel therapeutic and preventative strategies.

Image of a figure

Other collagens and disease: Collagen III and vascular Ehlers Danlos Syndrome V

Based on our expertise with collagen IV, we are currently expanding our work into other mechanisms and collagens. In collaboration with Profs. Neil Bulleid (Institute of Molecular, Cell and Systems Biology, Glasgow) and Fransiska Malfait (Centre Medical Genetics, Ghent) we have ongoing projects investigating mutations in the gene COL3A1 (collagen III) and vascular Ehlers Danlos Syndrome, a genetic connective tissue disorders that leads to arterial dissection and rupture. We employ different systems to determine the molecular mechanisms by which these mutations cause vEDS and aortic aneurysm formation.

In addition, we are continuously considering other disease to which we can apply our expertise in cell-matrix biology.

Publications

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Number of items: 27.

2021

Pokhilko, A. et al. (2021) Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease. Journal of Cerebral Blood Flow and Metabolism, 41(9), pp. 2423-2438. (doi: 10.1177/0271678X211004307) (PMID:33730931)

Boland, E., Quondamatteo, F. and Van Agtmael, T. (2021) The role of basement membranes in cardiac biology and disease. Bioscience Reports, 41(8), BSR20204185. (doi: 10.1042/bsr20204185) (PMID:34382650)

Chung, J. et al. (2021) Rare missense functional variants at COL4A1 and COL4A2 in sporadic intracerebral hemorrhage. Neurology, 97(3), e236-e247. (doi: 10.1212/WNL.0000000000012227) (PMID:34031201)

Randles, M. et al. (2021) Identification of an altered matrix signature in kidney aging and disease. Journal of the American Society of Nephrology, 32(7), pp. 1713-1732. (doi: 10.1681/ASN.2020101442) (PMID:34049963)

Reuten, R. et al. (2021) Basement membrane stiffness determines metastases formation. Nature Materials, 20(6), pp. 892-903. (doi: 10.1038/s41563-020-00894-0) (PMID:33495631)

Schofield, C. L., Rodrigo-Navarro, A. , Dalby, M. J. , Van Agtmael, T. and Salmeron-Sanchez, M. (2021) Biochemical– and biophysical–induced barriergenesis in the blood brain barrier: a review of barriergenic factors for use in in vitro models. Advanced NanoBiomed Research, 1(5), 2000068. (doi: 10.1002/anbr.202000068)

2020

Dean, A. and Van Agtmael, T. (2020) Collagen IV related disease and therapies. In: The Collagen Superfamily and Collagenopathies. Springer. (Accepted for Publication)

Ngandu Mpoyi, E. et al. (2020) Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts. Biomaterials, 252, 120090. (doi: 10.1016/j.biomaterials.2020.120090) (PMID:32413593)

2019

Gatseva, A., Sin, Y. Y., Brezzo, G. and Van Agtmael, T. (2019) Basement membrane collagens and disease mechanisms. Essays in Biochemistry, 63(3), pp. 297-312. (doi: 10.1042/EBC20180071) (PMID:31387942) (PMCID:PMC6744580)

Jones, F. E. et al. (2019) 4-Sodium phenyl butyric acid has both efficacy and counter-indicative effects in the treatment of Col4a1 disease. Human Molecular Genetics, 28(4), pp. 628-638. (doi: 10.1093/hmg/ddy369) (PMID:30351356) (PMCID:PMC6360271)

2018

Horsburgh, K. et al. (2018) Small vessels, dementia and chronic diseases – molecular mechanisms and pathophysiology. Clinical Science, 132(8), pp. 851-868. (doi: 10.1042/CS20171620) (PMID:29712883)

2017

Wang, D., Mohammad, M., Wang, Y., Tan, R., Murray, L. S., Ricardo, S., Dagher, H., van Agtmael, T. and Savige, J. (2017) The chemical chaperone, PBA, reduces ER stress and autophagy and increases collagen IV α5 expression in cultured fibroblasts from men with X-linked Alport syndrome and missense mutations. Kidney International Reports, 2(4), pp. 739-748. (doi: 10.1016/j.ekir.2017.03.004)

2016

Verdura, E. et al. (2016) Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy. Annals of Neurology, 80(5), pp. 741-753. (doi: 10.1002/ana.24782) (PMID:27666438)

Jones, F. E. et al. (2016) ER stress and basement membrane defects combine to cause glomerular and tubular renal disease resulting from Col4a1 mutations in mice. Disease Models and Mechanisms, 9(2), pp. 165-76. (doi: 10.1242/dmm.021741) (PMID:26839400) (PMCID:PMC4770143)

2015

Rannikmäe, K. et al. (2015) Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology, 84(9), pp. 918-926. (doi: 10.1212/WNL.0000000000001309) (PMID:25653287) (PMCID:PMC4351667)

2014

Husi, H., Van Agtmael, T. , Mullen, W. , Bahlmann, F. H., Schanstra, J. P., Vlahou, A., Delles, C. , Perco, P. and Mischak, H. (2014) Proteome-based systems biology analysis of the diabetic mouse aorta reveals major changes in fatty acid biosynthesis as potential hallmark in diabetes mellitus-associated vascular disease. Circulation: Cardiovascular Genetics, 7(2), pp. 161-170. (doi: 10.1161/CIRCGENETICS.113.000196)

Murray, L.S., Lu, Y., Taggart, A., Van Regemorter, N., Vilain, C., Abramowicz, M., Kadler, K.E. and Van Agtmael, T. (2014) Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke. Human Molecular Genetics, 23(2), pp. 283-292. (doi: 10.1093/hmg/ddt418) (PMID:24001601) (PMCID:PMC3869351)

2011

Agarwal, S., Taylor, S.H., Al-Youha, S., Van Agtmael, T. , Lu, Y., Wong, J., McGrouther, D.A. and Kadler, K.E. (2011) Tendon is covered by a basement membrane epithelium that is required for cell retention and the prevention of adhesion formation. PLoS ONE, 6(1), e16337. (doi: 10.1371/journal.pone.0016337)

2010

Van Agtmael, T. , Bailey, M. A., Schlotzer-Schrehardt, U., Craigie, E., Jackson, I. J., Brownstein, D. G., Megson, I. L. and Mullins, J. J. (2010) Col4a1 mutation in mice causes defects in vascular function and low blood pressure associated with reduced red blood cell volume. Human Molecular Genetics, 19(6), pp. 1119-1128. (doi: 10.1093/hmg/ddp584)

Van Agtmael, T. and Bruckner-Tuderman, L. (2010) Basement membranes and human disease. Cell and Tissue Research, 339(1), pp. 167-188. (doi: 10.1007/s00441-009-0866-y)

2009

Alamowitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Van Agtmael, T. , Marro, B. and Ronco, P. (2009) Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurology, 73(22), pp. 1873-1882. (doi: 10.1212/WNL.0b013e3181c3fd12)

2007

Plaisier, E. et al. (2007) COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. New England Journal of Medicine, 357(26), pp. 2687-2695. (doi: 10.1056/NEJMoa071906)

2005

Van Agtmael, T. (2005) Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy. Human Molecular Genetics, 14(21), pp. 3161-3168. (doi: 10.1093/hmg/ddi348)

2004

Van Agtmael, T. (2004) 17th International Mouse Genome Conference. Mammalian Genome, 15(7), pp. 509-514. (doi: 10.1007/s00335-004-4001-9)

2003

Van Agtmael, T. (2003) Parametric and nonparametric genome scan analyses for human handedness. European Journal of Human Genetics, 11(10), pp. 779-783. (doi: 10.1038/sj.ejhg.5201048)

2002

Van Agtmael, T. (2002) Parametric and non-parametric linkage analysis of several candidate regions for genes for human handedness. European Journal of Human Genetics, 10(10), pp. 623-630. (doi: 10.1038/sj.ejhg.5200851)

2001

Van Agtmael, T. (2001) Genes for left-handedness: How to search for the needle in the haystack? Laterality, 6(2), pp. 149-164. (doi: 10.1080/713754403)

This list was generated on Sat Oct 16 13:46:51 2021 BST.

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