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Dr Shanie Budhram-Mahadeo
414
MMBU, Rayne Building
5 University Street
London
United Kingdom
WC1E 6JF
Appointment
  • Reader in Molecular and Cellular Biology
  • Pre-clinical & Fundamental Science
  • Institute of Cardiovascular Science
  • Faculty of Pop Health Sciences
Biography

Dr Vishwanie (Shanie) Mahadeo is employed at University College London (UCL) as a Lecturer and Principal Investigator in the Medical Molecular Biology Unit (MMBU) and has been leading an independent and active research group since 1999. 

She graduated with BSc Honours in Medical Biophysics (2:1) in 1990 (University of East London) and PhD in Biochemistry and Molecular Biology at University College London (1992-1995). Previous research employment included research assistantship (Royal Postgraduate Medical School, Imperial College London 1990-1991), postdoctoral research fellowship (UCL Medical School, 1996-1999) and internship at INSERM, Strasbourg, France (1997). In 1999, she was appointed  Lecturer in Medical Molecular Biology (UCL Institute of Child Health) and Honorary Clinical Scientist (Great Ormond Street Hospital).

Dr Mahadeo's research group has focused on elucidating the molecular mechanisms controlling gene expression and cell fate in different physiological systems. These studies have identified novel functions for related Brn-3a and Brn-3b transcription factors (originally identified in MMBU laboratory) in controlling genes that drive diverse cellular processes (proliferation, differentiation, apoptosis) and identified changes that contribute to diseases (cancer, heart disease and type II diabetes). This research also established a novel paradigm to explain how complex cellular processes are controlled by interactions between different classes of transcription factors.

She has co-authored 62 publications including 47 peer-reviewed publications (12 as senior author; 13 as first author) in prestigious scientific journals e.g. J Biol Chem, Cancer Research, Oncogene, Mol Cell Biol and Cell Death Differentiation. She has been invited to present scientific findings at international and national conferences and was the invited guest speaker to discuss “Genes and Cancer” on television health programme “Your Life in Your Hands” in Guyana, South America.

Dr Mahadeo has won peer-reviewed grand funding from funding bodies including British Heart Foundation, The Rosetrees Trust,  Dunhill Medical Trust, Breast Cancer Campaign, Association for International Cancer Research, The Neuroblastoma Society and Child Health Research Action Trust (CHRAT) Studentship. She also supervised research fellows and research assistants employed by these funds.

She has also been actively involved in postgraduate teaching at UCL, undertaking formal lectures and tutorials and postgraduate supervision (4 PhD students as primary supervisor and 5 PhD students as co-supervisor, 10 MSc / MRes students) as well as providing opportunities for undergraduate and work experience students She also undertakes administrative duties (MMBU manager, GMO officer, HTA representative) and has served on advisory committees [Rayne Users Group Committee (current), UCL Academic Board elected non- professorial member (2002- 2012), CHRAT studentships review committee (2000-2003, 2005-2007)].

In recognition of expertise in her field of research, Dr Mahadeo has provided reviews for manuscripts for scientific journals (Nucleic Acids Research, Oncogene, Journal of Biological Chemistry, Journal of Pathology, Cell Death Disease) and project grant applications (funding bodies including Medical Research Council, Wellcome Trust, British Heart Foundation, Rosetrees Trust, Breast Cancer Campaign, Association of International Cancer Research).

As an expert in specific areas of research, Dr Mahadeo has also acted as examiner for PhD student at international institutes (University of Copenhagen, Denmark) and nationally (Manchester University, Bart’s and Queen Mary, University of London) or as internal examiner for UCL PhD and MD students.

Research Summary

Transcriptional regulation of gene expression in health and disease -

POU IV homeodomain transcription factors:

Research in MMBU has focused on analysing the expression/effects of distinct but related tissue-specific transcription factors (TFs), POU4F1/Brn-3a and POU4F2/Brn-3b, in health and disease. These proteins act as master regulators to control the rate of transcription of specific genes by the RNA polymerase II enzymes. By controlling the expression of multiple target genes such regulators can profoundly affect cell fate. Evidence from our studies have implicated altered expression of these TFs in human diseases. For example, elevated Brn-3b can contribute to tumour growth in some breast cancers and childhood neuroblastomas by activating cell cycle proteins, cyclin D1/CDK4 and repressing BRCA1 tumour suppressor protein. However, Brn-3b can also confer drug resistance and migratory potential to cancer cells following treatment with cytotoxic drugs by activating HSP27. 

Brn-3a and Brn-3b are highly conserved proteins, encoded by different genes but share >95% homology in the DNA binding POU domain and so recognise and bind to similar DNA sequences in target gene promoters. As such, these TFs may have similar effects on some genes (e.g. both Brn-3a and Brn-3b transactivate HSP27 promoter), thereby partially compensating for each other in some tissues/conditions. However, differences outside of the POU domain can give rise to complex, antagonistic effects on other target genes that affect cell fate, which depend on the cell type/growth conditions and co-expression of other cellular factors with which they interact. For example, both Brn-3a and Brn-3b interact with p53, but Brn-3a promotes cell survival by blocking p53-mediated transcription of pro-apoptotic Bax /Noxa genes whilst cooperating with p53 to activate p21cip1/waf1 cell cycle inhibitor. In contrast, if co-expressed, Brn-3b cooperates with p53 to increase pro-apoptotic Bax, thereby enhancing apoptosis. However, in the absence of p53, Brn-3b can drive cell proliferation. Since these regulators can profoundly alter cell fate, it is important to analyse their mechanisms of action in specific cellular context.

Although originally isolated from neuronal/neuroblastoma cells, Brn-3a and Brn-3b are expressed in diverse tissues including central/peripheral nervous system, heart, skeletal muscle, smooth muscle, epithelial cells, testis and T cells. These proteins have been extensively researched in specific subsets of neuronal cells but their functions in other non-neuronal tissues are not known. Yet data from mutant mice and other genetic studies suggest important roles for these transcriptional regulators in other tissues that are linked to common human diseases such as cancers and cardiovascular diseases. At present, our research is focused on investigating the roles for Brn-3a and Brn-3b in cardiovascular development and disease and potential links with metabolic dysfunction such as obesity and type II diabetes.

Current research includes:
1.    Analysing roles for Brn-3a and Brn-3b in adult hearts in response to stress/injury using mouse models of acute injury (coronary artery ligation) or chronic stress (AngII infusion or aortic banding).
2.    Investigate potential compensatory roles of Brn-3a and Brn-3b in the heart using conditional KO mutant mice and transgenic zebrafish models (generated using CrispR/cas 9 gene editing).
3.    Elucidate essential roles for Brn-3b in maintaining vascular integrity /function 
4.    Linking cardio-metabolic dysfunction with loss of Brn-3b expression by immuno-phenotyping Brn-3b KO mice.
Teaching Summary

Formal Lectures
- MRes in Biomedicine and MSc Molecular Medicine
- ‘Transcription Factors in control of gene expression’
- ‘Methods to study Transcription Factors’
- Tutorial ‘Proteins involved in DNA replication and transcription’

Postgraduate Teaching:
Primary supervisor for 4 postgraduate PhD students (UCL) – (3 completed PhD’s and one ongoing BHF funded student).

Co-supervisor of 4 postgraduate PhD students at UCL.

Co-supervised 1 PhD student from University of Pisa, Italy

Supervised 10 postgraduate MSc and MRes students lab-based projects

Supervised 7 undergraduate students (summer students or work experience students.

Primary supervisor for 4 research fellows and 4 research assistants in MMBU

Appointments
01-SEP-1999 Lecturer Medical Molecular Biology Unit UCL Institute of Child Health, University College London, United Kingdom
01-JAN-1996 – 31-AUG-1999 Research Fellow   UCL Windeyer Medical School, United Kingdom
Academic Background
1995 PhD Doctor of Philosophy – Biochemistry University of London
1990 BSc Hons Bachelor of Science (Honours) – Medical Biophysics University of East London
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