Research

Dr. Lorena Fernández-Martínez’s research in the Biology Department at Edge Hill University

Research in my laboratory is focused on understanding the production of natural products from Actinomycetes. Actinomycetes are a wonderful and diverse group of gram positive bacteria present in almost all environments. In particular my research group is interested in the genus Streptomyces because this genus alone is responsible for the production of a high number of clinically relevant specialised metabolites including antibiotics, anti-fungal, anti-helminthic and anti-cancer drugs.

By understanding how these medically relevant compounds are made by the producing organism, we can manipulate these biosynthetic pathways and therefore increase their yield. This is essential for industry as in order to undergo clinical trials, biotechnology companies need to be able to obtain high quantities of the purified new drug to be tested.

We also have an interest on how these industrially relevant Streptomyces strains develop in their natural environment. Streptomyces contain an arsenal of specialised metabolite clusters which are not expressed under laboratory conditions. We aim to understand more about their ecological niche as well as how interactions with other organisms affect development and specialised metabolite production.

We use a wide range of techniques in order to study the production of these specialised metabolites and the biology of these fascinating organisms including molecular genetics techniques such as cloning, heterologous expression, directed mutagenesis and gene deletion combined with enzymatic assays, microscopy, DNA and RNA sequencing and bioinformatic approaches.

Current projects

Identification of natural products from Colombian Actinomycetes: understanding their biosynthesis towards the discovery and production of novel antimicrobials.

This Newton Institutional Links funded project has developed on to an EHU funded PhD studentship in which Lina Pintor-Escobar is trying to identify new antibiotics from three Colombian Streptomyces strains.

Back to Soil: awakening the production of cryptic antibiotics in Streptomyces strains

In this BBSRC funded project, Dr Jana Schniete and Joey Paros are investigating the regulation of antibiotic gene clusters under soil conditions, particularly in industrially relevant strains, as this will help us understand how the production of these compounds is regulated in a more natural environment. Expression of most of these antibiotic gene clusters appears dormant (cryptic) under laboratory conditions but the clusters are maintained in the genomes of these strains, therefore indicating that they must play important roles in adaptation and survival within their ecological niches. These cryptic pathways represent an untapped resource in terms of new metabolites and novel chemistry that could be very useful in the clinic.

Recent projects

The effect of seasonal change on the distribution of antibiotic producing Actinomycete communities across a coastal transect

In this project MRes candidate Gillian Lewis tried to understand the effect of seasonal variation on production of metabolites in Actinomycetes.

The build-up of antibiotic resistance across different land uses in the UK

In this MRes project Kieran Osbiston explored whether there is a link between land use and antibiotic resistance levels in the soil using samples from sites across the North West of England.

This research group is interested in rare, genetic diseases which affect the epidermis. We seek to understand the cause of these diseases^1-5, study differences in skin function and develop new patient-specific therapeutics for these orphan diseases.

One main interest for research is topical drug development for autosomal recessive congenital ichthyosis (ARCI), a very rare condition which affects roughly 800 persons in the UK (prevalence is 1 to 100,000 persons in the UK and the EU). ARCI can be life-threatening at birth. It is life-long condition with currently only limited and not sufficient therapy options.

Find out more

Interesting and useful links:

• Ichthyosis Support Group
• NHS – Ichthyosis
• European Network for Ichthyosis

Lab facilities

View into cell culture incubator in our laboratory with primary human keratinocytes, fibroblasts and melanocytes from healthy control donors and patients cultured at 37°C, 90% humidity and 5% CO_2. Samples are cultured with permission from Edge Hill University ethical commission (URESC), and all samples have been collected only after written consent has been granted.

An immune-fluorescence-cyto-chemistry (ICC) straining of keratinocytes grown and fixed on small cover slips. Cells were stained against keratin 10 (red) and GM130 (green) and counterstained with Dapi (blue). Keratin 10 is only expressed in differentiated keratinocytes. GM130 shows the Golgi apparatus within a cell and Dapi localises the DNA (nuclei).

We are proud to have a brand-new and state of the art histology suite. Standard procedures including H&E or Fontana-Masson staining are performed in these standard jars.

ARCI Drug project

To develop new therapies for ARCI we have, together with British and international co-operation partners developed strategies to develop and advance new drugs for our patients (topical protein replacement therapy) 6-8. New drugs are tested on 3D skin models we generate in-house9 and reduce the use of animals in our research significantly.

Melanocyte project

We are also interested in the role of melanocytes (pigmented cells in the skin – these are the cells which allow tanning). Melanocytes play a role in rare skin diseases and are responsible for melanoma development. We are currently studying patient and healthy melanocytes in various studies to further our knowledge in pigmentation disorder origins (for example Neurofibromatosis, trichothiodystrophy, or vitiligo).

ARCI Epigenetics project

Tremendous progress has been made in recent years in the epigenetic understanding of the epidermis, which is a highly complex, ever changing tissue, with keratinocytes moving from the basal layer to the outermost layer during a process called “terminal differentiation”. This differentiation requires a highly orchestrated gene expression profile with genes switched on and off in each layer of the epidermis and if a gene is absent from this protocol due to a mutation (e.g. in ARCI patients), the process might be severely inhibited or changed. But not only gene expression is tightly controlled but also DNA methylation but also histone modifications. We have recently published our first preliminary results on how true mutations affect epidermal epigenetic profiles between healthy and ARCI patients.

References

1. Eckl, K.M., Krieg, P., Kuster, W., Traupe, H., Andre, F., Wittstruck, N., Furstenberger, G., and Hennies, H.C. (2005). Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Hum Mutat 26, 351-361.
2. Eckl, K.M., de Juanes, S., Kurtenbach, J., Natebus, M., Lugassy, J., Oji, V., Traupe, H., Preil, M.L., Martinez, F., Smolle, J., et al. (2009). Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis: Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B. J Invest Dermatol 129, 1421-1428.
3. Oji, V., Eckl, K.M., Aufenvenne, K., Natebus, M., Tarinski, T., Ackermann, K., Seller, N., Metze, D., Nurnberg, G., Folster-Holst, R., et al. (2010). Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease. AmJHumGenet 87, 274-281.
4. Blaydon, D.C., Nitoiu, D., Eckl, K.M., Cabral, R.M., Bland, P., Hausser, I., van Heel, D.A., Rajpopat, S., Fischer, J., Oji, V., et al. (2011). Mutations in CSTA, Encoding Cystatin A, Underlie Exfoliative Ichthyosis and Reveal a Role for This Protease Inhibitor in Cell-Cell Adhesion. Am J Hum Genet 89, 564-571.
5. Eckl, K.M., Tidhar, R., Thiele, H., Oji, V., Hausser, I., Brodesser, S., Preil, M.L., Onal-Akan, A., Stock, F., Muller, D., et al. (2013). Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length. JInvest Dermatol 133, 2202-2211.
6. Alnasif, N., Zoschke, C., Fleige, E., Brodwolf, R., Boreham, A., Ruhl, E., Eckl, K.M., Merk, H.F., Hennies, H.C., Alexiev, U., et al. (2014). Penetration of normal, damaged and diseased skin – An in vitro study on dendritic core-multishell nanotransporters. JControl Release 185, 45-50.
7. Eckl, K.M., Weindl, G., Ackermann, K., Kuchler, S., Casper, R., Radowski, M.R., Haag, R., Hennies, H.C., and Schafer-Korting, M. (2014). Increased cutaneous absorption reflects impaired barrier function of reconstructed skin models mimicking keratinisation disorders. Exp Dermatol 23, 286-288.
8. Witting, M., Molina, M., Obst, K., Plank, R., Eckl, K.M., Hennies, H.C., Calderon, M., Friess, W., and Hedtrich, S. (2015). Thermosensitive dendritic polyglycerol-based nanogels for cutaneous delivery of biomacromolecules. Nanomedicine, 10.
9. Eckl, K.M., Alef, T., Torres, S., and Hennies, H.C. (2011). Full-Thickness Human Skin Models for Congenital Ichthyosis and Related Keratinization Disorders. J Invest Dermatol 131, 1938-1942.
10. Aufenvenne, K., Larcher, F., Hausser, I., Duarte, B., Oji, V., Nikolenko, H., Del, R.M., Dathe, M., and Traupe, H. (2013). Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts. AmJHumGenet 93, 620-630.
11. Aufenvenne, K., Rice, R.H., Hausser, I., Oji, V., Hennies, H.C., Rio, M.D., Traupe, H., and Larcher, F. (2012). Long-term faithful recapitulation of transglutaminase 1-deficient lamellar ichthyosis in a skin-humanized mouse model, and insights from proteomic studies. JInvest Dermatol 132, 1918-1921.
12. Eckl, K.M. (2014). Update: advanced methods in three-dimensional organotypic tissue engineering for congenital ichthyosis and other rare keratinization disorders. Br J Dermatol 171, 1289-1290.
13. Sommer, C.A., Stadtfeld, M., Murphy, G.J., Hochedlinger, K., Kotton, D.N., and Mostoslavsky, G. (2009). Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells 27, 543-549.
14. Berggren, W.T., Lutz, M., and Modesto, V. (2014). General Spinfection Protocol. (Cambridge (MA), Harvard Stem Cell Institute.

Recent abstracts and conference papers

1. Eckl K, Tidhar R, Thiele H, Oji V, Hausser I, Brodesser S, Preil ML, Önal-Akan A, Stock F, Altmüller J, Nürnberg P, Traupe H, Futerman AH, Hennies HC, Mutations in CERS3 lead to autosomal recessive ichthyosis and demonstrate the importance of ceramides in healthy and ichthyotic skin. J Invest Dermatol 133:S138 (2013)
2. Weindl G, Eckl KM, Ackermann K, Küchler S, Casper R, Radowski MR, Haag R, Hennies HC, Schäfer-Korting M, Increased cutaneous absorption reflects impaired barrier function of reconstructed skin models mimicking keratinisation disorders. European Society for Alternatives to Animal Testing 15th Annual Conference (2013)
3. Eckl KM, de Lima Cunha DM, Plank R, Lechner S, Casper R, Rauch M, Fatima A, Saric T, Hennies HC, The long road to the ectodermal fate – Patient specific iPS-cell derived keratinocytes. Austrian Society for Human Genetics, 13th Annual Meeting (2013)
4. Eckl KM Tidhar R, Thiele H, Oji V, Hausser I, Brodesser S, Preil ML, Önal-Akan A, Stock F, Altmüller J, Nürnberg P, Traupe H, Futerman AH, Hennies HC, Autosomal Recessive Congenital Ichthyosis (ARCI) and related disorders: Mutation in CERS3, coding for ceramide synthase 3, reveal major puzzle pieces for the understanding of epidermal barrier formation. American Society of Human Genetics 63nd Annual Meeting (2013)
5. de Lima Cunha D, Eckl KM, Rauch M, Casper R, Gupta MK, Alnutaifi K, Gruber R, Schmuth M, Kakar N, Borck G, Stieler K, Krabichler B, Lingenhel A, Zschocke J, Nürnberg P, Mostoslavski G, Saric T, Hennies HC, Genetic heterogeneity of congenital ichthyosis and the use of iPS cells to study rare genetic skin diseases. Med Genet 26:183 (2014)
6. Plank R, Rauch M, Casper R, Küchler S, Eckl KM, Hennies HC, Protein substitution in keratinocytes for enzyme replacement therapy in autosomal recessive congenital ichthyosis. Med Genet 26:204 (2014)
7. Eckl KM, de Lima Cunha DM, Casper R, Stieler K, Oji V, Traupe H, Rauch M, Lingenhel A, Fauth C, Gupta MK, Saric T, Hennies HC, iPS-cell derived basal keratinocytes for autosomal recessive congenital ichthyosis. Med Genet 26:104 (2014)
8. de Lima Cunha D, Eckl KM, Rauch M, Casper R, Kumar Gupta M, Nürnberg P, Schmuth M, Zschocke J, Saric T, Hennies HC, Generation and characterization of induced pluripotent stem (iPS) cells from autosomal recessive congenital ichthyosis patients – A new model system to study rare skin keratinization disorders. J Invest Dermatol 134:S34 (2014)
9. Plank R, Rauch M, Casper R, Obst K, Küchler S, Eckl KM, Hennies HC, 3D skin models for protein substitution in autosomal recessive congenital ichthyosis. J Invest Dermatol 134:S54 (2014)
10. de Lima Cunha D, Eckl KM, Rauch M, Casper R, Kumar Gupta M, Schmuth M, Zschocke J, Saric T, Hennies HC, Patient-specific induced pluripotent stem cells for model systems to study congenital skin diseases. Austrian Society for Human Genetics, 14th Annual Meeting (2014)
11. Eckl KM, Pavlovsky M, Plank R, Küchler S, Sprecher E, de Lima Cunha DM, Casper R, Hennies HC, Don’t harm the animals – Update on advanced alternatives in personalised therapy development for genetic disorders. Austrian Society for Human Genetics, 14th Annual Meeting (2014)
12. Plank R, Rauch M, Casper R, Obst K, Küchler S, Eckl KM, Hennies HC, Protein replacement in autosomal recessive congenital ichthyosis: Recombinant TGase-1 substitutes enzyme activity in 3D disease skin models. Austrian Society for Human Genetics, 14th Annual Meeting (2014)
13. Eckl KM, de Lima Cunha DM, Plank R, Casper R, Traupe H, Rauch M, Gupta MK, Saric T, Hennies HC, iPS-cell derived basal keratinocytes and melanocytes to study severe monogenic genodermatoses in patient-specific 3D tissue systems. American Society of Human Genetics 64th Annual Meeting (2014)
14. Plank R, Casper R, Schupart R, Obst K, Hermann M, Hedtrich S, Eckl KM, Hennies HC, Cutaneous enzyme delivery for a novel personalized protein replacement therapy for patients with autosomal recessive congenital ichthyosis (ARCI). Med Genet 27:183-184 (2015)
15. Lima Cunha D, Eckl KM, Casper R, Schupart R, Lingenhel A, Gupta M, Mostoslavski G, Saric T, Hennies HC, Induced pluripotent stem cell-derived keratinocytes for patient specific models of monogenic keratinization disorders. Med Genet 27:183 (2015)
16. Werner R, Schossig A, Eckl KM, Krabichler B, Thiele H, Nürnberg P, Zschocke J, Hennies HC, Kapferer-Seebacher I. Molecular Basis of Aggressive Periodontitis. Med Genet 27:174 (2015)
17. Eckl KM, de Lima Cunha, D, Saric T, Hennies HC Pigmented 3D skin models made from patient-specific iPS cell-derived melanocytes. Human Genetics 66th Annual Meeting (2016)
18. De Lima Cunha D, Alakloby OM, Eckl KM, Rauch M, Casper R, Kakar N, Krabichler B, Gruber R, Altmüller J, Nürnberg P,  Zschocke J, Borck G, Schmuth M,  Alnutaifi KA,  Alabdulkareem AS, and Hennies HC. New mutations and genotype/phenotype correlation in patients from consanguineous families from Saudi Arabia and Pakistan with different forms of autosomal recessive congenital ichthyosis. Human Genetics 66th Annual Meeting (2016)
19. Plank R, Casper R, Schupart R, Obst K, Hermann M, Hedtrich S, Eckl KM, and Hennies HC.Protein substitution therapy for autosomal recessive congenital ichthyosis (ARCI). Med Genet 29 (2017)
20. Cunha D, Golding K, Tahir H, Barragán Vázquez^, I, Saric T, Ploner C, Hennies HC, Eckl KM. TP63 is expressed in adult epidermal and iPSC-derived melanocytes supporting the role ofΔNp63 in ectodermal gatekeeping and cell migration to the epidermis. Am Human Genetics 67^th Annual Meeting (2017)
21. Barragán Vázquez^, I, Cunha, Hockney S, Tang KY, Thomforde Kitson S, Eckl KM, Hennies HC. The role of p63 isoforms in the epidermal development as replicated in cellular models for normal human skin and genetic skin diseases. Am Human Genetics 67^th Annual Meeting (2017)

The Mosquitos (Culicidae) of Great Britain

Thom Dallimore and Dr Clare Strode

Ecological genetics of Tilia cordata

Carl Barker

Ecological Epigenetics of Tilia Cordata

Carl Barker

Ecology and conservation status of temporary ponds in two areas of southern England

Alan Bedford

Characteristics of Tilia cordata (Small Leaved Lime) at its Range Margins and their Implications in View of Climate Change

Clare Bugg

Dispersal Ecology of Collembola (Springtails)

Thomas Dallimore

Origins of the disjunct distribution of the Estuarine sedge (Carex recta)

Mary Dean

The Mosquitos (Culicidae) of Great Britain

Thom Dallimore and Dr Clare Strode

The contribution of Tropical Epiphytes to Hydrological cycle

Dr Sven Batke

Next Generation Plant Technologies

Dr Sven Batke