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Molecular Basis of Disease

Research in the Molecular Basis of Disease research group follows a multi-disciplinary and highly collaborative approach to increase understanding of disease at a molecular level in order to improve diagnosis and treatment. This includes a range of infectious and chronic diseases in animals and humans. The Group has developed strong links with research groups in the School of Computer Science and School of Engineering, and other Institutes and Universities within the UK and abroad.

The group receives research funding from the BBSRC, Royal Society and British Heart Foundation.

 

Diabetes Research

Research into key diabetes themes: The cellular and molecular aspects of diabetes, pancreatic islet cell development and function, immunology of Type 1 diabetes and pathogenesis of diabetic complications.

Name Position/Research interests
Dr Csanad Bachrati Reader
Molecular cell biology
cbachrati@lincoln.ac.uk
01522 886787
Dr Tim Bates Senior Lecturer
Cancer, pharmacology, toxicology, metabolism and cellular pathology
tbates@lincoln.ac.uk
01522 837144
Dr Stephen Bevan Deputy Head of School
Genetics, genetic analysis, complex disease genetics
sbevan@lincoln.ac.uk
01522 886970
Dr Colin Butter Reader in Bioveterinary Science
Avian and comparative immunology
cbutter@lincoln.ac.uk
Dr Michael Christie Reader
Pathophysiology of the pancreatic beta cell
mchristie@lincoln.ac.uk
01522 837434
Dr Nicola Crewe Senior Lecturer
Microbiology, molecular biology, microscopy
ncrewe@lincoln.ac.uk
01522 837424
Dr Ron Dixon Reader
Microbiology, molecular biology, pharmaceutical and biotechnology
rdixon@lincoln.ac.uk
01522 886891
Dr Enrico Ferrari Senior Lecturer
Nanobiotechnology
eferrari@lincoln.ac.uk
01522 886302
Dr James Flint Senior Lecturer
Biotechnology, molecular biology, biochemistry
jflint@lincoln.ac.uk
01522 886804
Dr Alan Goddard Senior Lecturer
Membrane protein biochemistry
agoddard@lincoln.ac.uk
01522 886864
Dr Humberto Gutierrez Senior Lecturer
Developmental Neurobiology, neuronal cell signalling, functional neurogenomics and evolution of brain complexity
hgutierrez@lincoln.ac.uk
01522 837078
Dr Claire Hills Senior Lecturer
Diabetes and endocrinology
chills@lincoln.ac.uk
Dr Neil Holden Senior Lecturer
Airway inflammatory diseases, asthma & COPD, virology and immunology
nholden@lincoln.ac.uk
01522 886014
Dr Issam Hussain Senior Lecturer
Stem cell biology, cancer and biomedical tissue engineering
ihussain@lincoln.ac.uk
01522 886992
Carolyn Johnson Postdoctoral Research Fellow in Diabetes
cjohnson@lincoln.ac.uk
Dr Clare Miller Senior Lecturer
Microbiology
cmiller@lincoln.ac.uk
01522 837364
Dr Stefan Millson Senior Lecturer
Use of yeast as a model system to study molecular chaperone "drivers" of cancer
smillson@lincoln.ac.uk
01522 886995
Dr Timea Palmai-Pallag Research Fellow
Molecular cell biology
tpalmaipallag@lincoln.ac.uk
01522 837429
Dr Carol Rea Principal Lecturer
Biomedical science, blood sciences
crea@lincoln.ac.uk
01522 886819
Prof Ciro Rinaldi Visiting Professor in Biomedical Science
Philadelphia negative myeloproliferative disorders
crinaldi@lincoln.ac.uk
Dr Peter Rose Senior Lecturer
Phytochemistry, natural products, drug discover, sulphur biochemistry
prose@lincoln.ac.uk
01522 886851
Dr Matthew Simmonds Senior Lecturer in Biomedical Science
Transplantation, autoimmunity, diabetes, autoimmune thyroid disease and genetics
msimmonds@lincoln.ac.uk
Dr Ishwar Singh Senior Lecturer
isingh@lincoln.ac.uk
01522 886915
Prof Paul Squires Professor in Biomedical Science
Diabetes and endocrinology
psquires@lincoln.ac.uk
Dr Edward Taylor Reader
Protein structure research
etaylor@lincoln.ac.uk
01522 837314
Dr Ross Williams Senior Lecturer
Microbiology, genetics, molecular biology, biotechnology, forensic science
rwilliams@lincoln.ac.uk
01522 886875

Molecular Oncology

The Molecular Oncology laboratory at Lincoln seeks to further the understanding of the molecular events behind cancer initiation and progression and the biochemical events involved in drug response in cancer cells. A fuller understanding these processes will lead to improved therapeutic strategies and thereby produce a more beneficial risk profile and outcome for patients. Major areas of research in the laboratory includes: genomic stability and DNA repair, Csanad Bachrati and Ishwar Singh, mitochondrial dysfunction, Tim Bates, leukaemic transformation and myeloproliferative neoplasms, Ciro Rinaldi and breast cancer metastasis, Issam Hussain. These research aims are achieved through molecular techniques and advanced proteomics and mass spectrometry.

• Advanced microscopy – AFM, SEM, confocal

• Recombinant protein expression and purification

• Microbiology CAT2 suite

• Cell culture

• Mitochondrial dysfunction in disease

• Mitochondrial pharmacology

• Mitochondrial toxicology

Current and recent research projects include:

GATA1 expression in MDS and its implication in azacitidine therapy

Erythroid cell dysplasia observed in early myelodysplastic syndromes (MDS) involves impairment of differentiation and excess of apoptosis with a burst of caspase activation and abnormal gene expression. Analysis of gene expression in MDS erythroblasts obtained by ex vivo cultures demonstrates the down-regulation of a set of GATA1 transcriptional target genes, including GYPA that encodes glycophorin A (GPA), and the up-regulation of members of the HSP70 family. Recent studies demonstrate steadily up-regulated RNA expression of GATA1 and BCLxl during late normal erythropoietic differentiation. In contrast, during MDS erythropoiesis, a loss of typical up-regulation of GATA1 and BCLxl was observed. Hypermethylation of CpG dinucleotides flanking the repressor HES1 binding site within the 5' region of GATA1 was detected particularly during late MDS erythropoiesis. Interestingly, decremental GATA1 promoter methylation values were seen during normal erythropoiesis matching GATA1 RNA up-regulation. Taken all the above, critical erythropoietic transcription factor GATA1 as well as the antiapoptotic molecule BCLxl fails to be normally up-regulated during MDS erythropoiesis. The higher residual 5'-GATA1 methylation values in MDS erythropoiesis but decremental loss thereof in normal erythropoiesis suggest a gene dose effect for GATA1 during erythropoiesis being finely tuned by CpG methylation. Its dysregulation may contribute to the ineffective erythropoiesis observed in MDS.

Azacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside used in DNA and RNA which has clearly shown efficacy in treatment of patients with MDS. Azacitidine is thought to induce antineoplastic activity via two mechanisms; inhibition of DNA methyltransferase at low doses, causing hypomethylation of DNA, and direct cytotoxicity in abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA at high doses, resulting in cell death. As azacitidine is a ribonucleoside, it incorporates into RNA to a larger extent than into DNA. The incorporation into RNA leads to the dissembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of protein. Its incorporation into DNA leads to a covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequent cytotoxicity.GATA1/BCLxL expression might represent a molecular marker in MDS. The levels of GATA1/BCLxL RNA might correlate with clinical outcome and response to treatment in particular with Azacitidine.

Ciro Rinaldi (£75,000)


Studies on the organelle-specific functions of human Type 1A topoisomerase TOP3A

DNA topoisomerases are ubiquitous enzymes with an indispensable function in maintaining the topology of DNA during replication, transcription and repair. In eukaryotes topoisomerases are involved in similar processes in the mitochondria as well as in the nucleus. The biochemical function and activities of TOP3A in vitro have been well characterised in recent years, but its cellular function still remains enigmatic. The project aims to understand the physiological role of TOP3A in the nuclei as well is in the mitochondria.     

Funded by a BBSRC New Investigator grant to Csanad Bachrati (£386,098)


GATA1 Expression levels in peripheral blood of patients with essential thrombocytaemia: implication for pathogenesis and treatment

GATA1, the founding member of the GATA transcription factor family, is essential for cell maturation and differentiation within the erythroid and megakaryocytic lineages. Several studies have suggested a connection between GATA1 and myeloproliferative disorders (MPDs). We studied the expression of GATA1 in bone marrow aspirates  of patients affected by MPDs and we found that GATA1 is significantly overexpressed in ET and PV. Anagrelide (Xagrid , Shire) has been proven to be active drug in reducing platelet count and thrombotic risk in management of MPD patients. In vitro studies indicate that Anagrelide suppresses GATA1 and its co-factor FOG1.  GATA1 levels on PB can be easily measured and might represent a new molecular marker to monitor the response and the residual disease during the cytoreductive therapy in particular with Anagrelide.

Funded by SHIRE grant to Ciro Rinaldi (£100,000)


Studies of the effects of anti-mitochondrial, pro-apoptotic drugs in cancer

Many drugs that are used to treat cancer were developed before the molecular mechanisms of mitochondrially-mediated apoptosis were delineated. Recent studies by our group have shown that several of these drugs have actions primarily on mitochondria. We are using a variety of cellular and molecular techniques to study mechanisms of cancer cell death, with a focus on how these drugs modulate mitochondrial function.


Developmental Neurobiology and functional neurogenomics

Nerve cells are unique in many ways. Most crucially, neurons require specialized maintenance mechanisms allowing them to survive and preserve their functional complexity for the entire life time of the organism and failure of these supporting mechanism lead to a wide range of degenerative conditions. The genomic bases of neuronal long term maintenance and functional stability are poorly understood. In order to identify novel genetic determinants of neuronal maintenance we are currently mining transcriptome data for a variety of human cell types with cellular longevities ranging from 120 days to 72 years to screen for genes whose expression levels are closely associated with increased cell longevity. Identifying the underlying maintenance mechanisms that allow long living tissues, such as nerve cells, to preserve their functional and structural integrity for the entire lifetime of the organism will be central four our understanding of aging and neurodegeneration in addition to the unique cell survival capabilities of the human nervous system.

Selected recent publications:

G Coceano, M S Yousafzai, W Ma, F Ndoye, L Venturelli, I Hussain, S Bonin, J Niemela, G Scoles, D Cojoc and E Ferrari. Investigation into local cell mechanics by atomic force microscopy mapping and optical tweezer vertical indentation. Nanotechnology 27, 65102 (2016)

Siamantouras E, Hills CE, Squires PE, Liu K-K. Quantifying cellular mechanics and adhesion in renal tubular injury using single cell force spectroscopy. Nanomedicine, 2016 in press. DOI: http://dx.doi.org/10.1016/j.nano.2015.12.362

Hills CE, Price GW, Squires PE. Mind the gap: connexins and cell-to-cell communication in the diabetic kidney. Diabetologia, 58 (2): 233-241, 2015.

Southgate, Laura and Sukalo, Maja and Karountzos, Anastasios S. V. and Taylor, Edward J. and Collinson, Claire S. and Ruddy, Deborah and Snape, Katie M. andDallapiccola, Bruno and Tolmie, John L. and Joss, Shelagh and Brancati, Francesco and Digilio, M. Cristina and Graul-Neumann, Luitgard M. and Salviati, Leonardo and Coerdt, Wiltrud and Jacquemin, Emmanuel and Wuyts, Wim and Zenker, Martin and Machado, Rajiv D. and Trembath, Richard C. (2015) Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver Syndrome with variable cardiac anomalies. Circulation: Cardiovascular genetics, 8 (4). ISSN 1942-325X

McLaughlin, Kerry A. and Gulati, Kavita and Richardson, Carolyn C. and Morgan, Diana and Bodansky, H. Jonathan and Feltbower, Richard G. and Christie, Michael (2014) HLA-DR4-associated T and B cell responses to specific determinants on the IA-2 autoantigen in type 1 diabetes. Journal of Immunology, 193 (9). pp. 4448-4456. ISSN: 0022-1767

Richardson, Carolyn and McLaughlin, Kerry and Morgan, Diana and Feltbower, Richard and Christie, Michael (2016) Influence of HLA-DR and -DQ alleles on autoantibody recognition of distinct epitopes within the juxtamembrane domain of the IA-2 autoantigen in type 1 diabetes. Diabetologia, 59(2), 334-340. ISSN: 0012-186X

Jason Arsenault, Sabine A. G. Cuijpers, Enrico Ferrar, Dhevahi Niranjan, Aleksander Rust, Charlotte Leese, John A. O'Brien, Thomas Binz and Bazbek Davletov. Botulinum protease-cleaved SNARE fragments induce cytotoxicity in neuroblastoma cells. J. Neurochem. 129, 781–91 (2014).

Nolan, Aoife M. and Collins, Louise M. and Wyatt, Sean L. and Gutierrez, Humberto and O'Keeffe, Gerard W. (2014) The neurite growth inhibitory effects of soluble TNFα on developing sympathetic neurons are dependent on developmental age. Differentiation, 88 (4-5). pp. 124-130.

Togher, K. L. and O'Keeffe, M. M. and Khashan, A. S. and Gutierrez, Humberto and Kenny, L. C. and O'Keeffe, G. W. (2014) Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development. Epigenetics, 9 (6). pp. 816-822.

Palmai-Pallag, Timea and Bachrati, Csanad (2014) Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle. Microbes and Infection, 16 (10). pp. 822-832.

Jason Arsenault, Enrico Ferrari, Dhevahi Niranjan, Sabine A. G. Cuijpers, Chunjing Gu, Yvonne Vallis, John O'Brien and Bazbek Davletov. Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells. J. Neurochem. 126, 223–33 (2013).

Enrico Ferrari, Chunjing Gu, Dhevahi Niranjan, Laura Restani, Christine Rasetti-Escargueil, Ilona Obara, Sandrine M. Geranton, Jason Arsenault, Tom A. Goetze, Callista B. Harper, Tam H. Nguyen, Elizabeth Maywood, John O’Brien, Giampietro Schiavo, Daniel W. Wheeler, Frederic A. Meunier, Michael Hastings, J. Michael Edwardson, Dorothea Sesardic, Matteo Caleo, Stephen P. Hunt and Bazbek Davletov. Synthetic Self-Assembling Clostridial Chimera for Modulation of Sensory Functions. Bioconjug. Chem. 24, 1750–1759 (2013)

We welcome applications at any time from prospective MSc by Research (MScRes), MPhil or PhD students wishing to join our thriving postgraduate research community. For further information on the range of research topics available, please see the individual staff pages and contact potential supervisors directly.

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School of Life Sciences, University of Lincoln, Brayford Pool, Lincoln. LN6 7TS 

email: enquiries@lincoln.ac.uk
tel: + 44 (0)1522 886654