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Dr Talat Nasim

PositionLecturer in Therapeutics
LocationNorcroft building, 2.12
DepartmentSchool of Pharmacy
Telephone+44 (0) 1274 236076
EmailT.Nasim@bradford.ac.uk

Research Interests (key words only)

Translational Medicine, Pulmonary Hypertension, Genetic Disorders, Alternative Splicing, Personalized Therapy and Drug Discovery

PhD Supervision

PhD students

Nahid Sharmin
Funded by the Commonwealth Scholarship Commission; 2014-2017

Gillian Durham (with Prof. T. Palmer)
Funded by the Commonwealth Scholarship Commission; 2016-2019

MSc students

Muna Amin
School of Biomedical Science; 2015-2016

Amiri Mukungu
School of Biomedical Science; 2015-2016

Teaching and Supervisory Responsibilities

Pharmacy (MPharm)

Unit lead:

  • Cardiovascular System 2, Transport 2- Unit 4
  • Foundation Studies 1, Unit 2 and 3 – Cell structure and components

Unit team member:

  • Cardiovascular System 1, Transport 1- Unit 2
  • Cardiovascular System 1, Transport 1- Unit 5
  • Cardiovascular System 1, Transport 1- Unit 7 and 8
  • Cardiovascular System 1, Transport 1- Unit 1

Student Selected Component:

  • t-strand (Research topics)
  • Capability in Pharmacy years 1, 2, 3 and 4

Personal Academic Tutor for 18 students

Biomedical Sciences

  • Human Physiology (1st year)
  • M.Sc in Biomedical Sciences (Research projects)

Study History

2000: PhD in Biochemistry and Applied Molecular Biology, University of Manchester, previously known as UMIST, UK)

Professional History

2013: Visiting Senior Research Fellow,, King’s College London

2008: Founder and Chief Adviser (Honorary), Centre for Health, Agriculture and Socio-economic Advancements (CHASA), Bangladesh

2008 -2013: Senior Research Fellow, NIHR Comprehensive Biomedical Research Centre, Faculty of Translational Medicine, & Dept. of Medical and Molecular Genetics, King’s College London, England

2006 - 2008: Research Associate, Dept. of Medical and Molecular Genetics, King’s College London, England & Dept. of Genetics, University of Leicester, England

2000-2006: Research Associate, Dept. of Biochemistry, University of Leicester, England

1994-1996: Post-graduate Research Fellow, University of Geneva, Switzerland

Professional Activities

  • Academic Adviser: Commonwealth Scholarship Commission (2015-2021)
  • Executive Member: Global Network of Bangladeshi Biotechnologists (GNOBB) (2016- )
  • Life Member: Global Network of Bangladeshi Biotechnologists (GNOBB)
  • Member: American Thoracic Society
  • Member: Biochemical Society (UK)

Research Areas

Investigation of BMP and TGFβ signalling events to resolve pulmonary arterial hypertension (PAH)

PAH is a devastating cardiovascular disorder caused by narrowing of blood vessels in the lungs and in the absence of therapy leads to right heart failure and death. We have established that nonsense mutations in the BMPR2 gene underlie the majority of the inherited forms of the disease. BMPR2 mutations contribute to stoichiometric imbalance in the receptor complex leading to dysfunctional signalling (Nasim et al., 2008, 2012). Mutations are also found in the SMAD family genes but they represent an infrequent cause of the disease (Nasim et al., 2011). Mutations in the BMPR2 gene potentiate TGFβ signalling (Nasim et al., 2012) and prostacyclins, the commonly used therapy for severe PAH inhibit this pathway (Ogo et al., 2013). Taken together these observations suggest that agents that inhibit the overactive TGFβ signalling and/or promote the BMP signalling may provide protection in PAH. We identified some small molecule agents that restore the balance between the TGFβ and BMP pathways and rescued abnormal proliferation and apoptosis in cell-based models of PAH (Siddiqui et al., 2013). Structure guided virtual screening identified additional compounds which elicited anti-TGFβ activity in cell-based assays. A number of ‘leads’ have been identified through a medicinal chemistry programme (unpublished data).

The major objectives of this part of research are to investigate (a) the molecular mechanisms by which the TGFβ signalling is activated in PAH, and (b) therapeutic resolution of PAH by chemical agents that restore the balance between BMP and TGFβ signalling pathways.

References

  • M.T. Nasim, T. Ogo, H.M. Chowdhury and R.C. Trembath. Human Mol Genetics (doi 10.1093/hmg/DDS073), 2012
  • M T. Nasim, T. Ogo, M. Ahmed, R. Randall, et al. Human Mutation 12:1385-89, 2011
  • M.T. Nasim, A.G. Ghouri, B.P. Patel, et al., Hum Mol Genet (11):1683-94, 2008
  • M. T. Nasim, S. Jaenecke, A. Belduz, et al., J. Biol. Chem. 275: 14646-14852, 2000
  • T. Ogo, H.M. Chowdhury, N.W. Morrell, R.C. Trembath and M.T. Nasim. (American Journal of Respiratory Cell and Molecular Biology), 2013.
  • M.A Siddiqui, M. Ahmed, T. Ogo, M. Hossain, H.M. Chowdhury, L.Long, F. Khan, N. W. Morrell, R.C. Trembath and M.T. Nasim (unpublished), 2013.

Therapeutic resolution of nonsense-associated genetic disorders by promotion of translation readthrough

There are more than 2500 genetic disorders including cystic fibrosis, muscular dystrophy and PAH caused by nonsense mutations. Agents that promote translation readthorugh may provide therapeutic intervention. We have established cell based assay system which is capable of screening drugs that promote translational readthorugh (Nasim et al., 2000, 2005, 2008 and patent applications). Using these techniques, hits have been identified through screening of a small molecule library, which are now being tested whether they rescue BMPR2-mediated cellular defects in PAH.

The major objectives of this part of research are to (a) identify agents that promote readthrough and (b) test whether promotion of readthrough by small molecule agents can provide protection in PAH and in other nonsense associated genetic disorders.

References

  • M.T. Nasim, A.G. Ghouri, B.P. Hum Mol Genet (11):1683-94, 2008.2. M.T. Nasim* and R.C. Trembath. Nucleic Acids Res. 33(7): e66 (8 pages), 2005. 3. M. T. Nasim, S. Jaenecke, A. Belduz, H. Kollmus, L. Flohe and J.E.G. McCarthy; J. Biol. Chem. 275: 14646-14852, 2000.

Breast cancer gene function study of Bangladeshi population

Breast cancer (BC) is the leading cause of cancer deaths among women worldwide, with an estimated 1.7 million cases and > 0.5 million deaths per year. BC is the most common cancer in Bangladeshi women and is predicted to be an increasingly important cause of morbidity and mortality in the next 20 years. To date, no population-based cancer registries or a central registry with comprehensive national cancer data is available. For Bangladeshi women with human epidermal growth factor receptor (HER2), estrogen receptor (ER) and progesterone receptor (PR) negative patients (~25%) have no effective targeted therapies. In addition, it is currently not known whether these patients carry mutations in either BRCA1 or BRCA2 genes as there is no genetic screening system available in Bangladesh. Mutations in other genes such as TP53, PTEN and CASP8 are also found in BC patients worldwide but their penetrance in Bangladeshi populations remains unknown. The major objective of this research is to determine the genetic landscape of Bangladeshi BC patients to inform better diagnosis, prognosis, treatment and counselling.

Development of personalized therapy for nonsense-associated genetic disorders

Two approaches are presently being studied to overcome nonsense-associated genetic disorders. Gene therapy, not least because of recognised vector toxicity, it is still far from achieving routine clinical success. The aim of the alternative approach is to promote translation readthrough by means of small molecule agents. These readthrough agents interfere with normal translation termination process and hence this route does not offer opportunities for the development of personalized therapy. Hence there is a need to develop personalized therapies aiming to decode the nonsense mutation without interfering with the normal translation termination.

RNA therapeutics (e.g. Formivisren, Pfizer; Pegaptanib, Eyetech) offer the opportunities for targets and diseases that are not treatable by current small molecule and antibody-based drugs. RNA-directed promotion of translation readthrough has been observed in natural selenoprotein genes (Nasim et al., 2000). We investigated the underlying mechanisms and found that RNA-guided promotion of readthrough in natural selenoprotein genes occurs through a non-processive mechanism (Nasim et al., 2000). As a continued effort, we developed novel enzyme and fluorescence-based reporter assays to identify agents that promote translation readthrough (Nasim et al 2008 and patent applied for) and developed novel RNA-based therapies which selectively decode the pathogenic nonsense mutations associated with Cystic Fibrosis, Duchene Muscular Dystrophy, Usher and Hurler syndrome.

The major objective of this research is to investigate the mechanisms of decoding of nonsense mutations aiming to develop personalized therapies for nonsense-associated genetic disorders.

References

  • M.T. Nasim, A.G. Ghouri, B.P. Hum Mol Genet (11):1683-94, 2008.2. M.T. Nasim* and R.C. Trembath. Nucleic Acids Res. 33(7): e66 (8 pages), 2005. 3. M. T. Nasim, S. Jaenecke, A. Belduz, H. Kollmus, L. Flohe and J.E.G. McCarthy; J. Biol. Chem. 275: 14646-14852, 2000.

Modulation of Splicing in human diseases

Identification of non-canonical factors regulating tissue-specific alternative splicing

Mutations in pre-mRNA splicing signals account for both inherited and acquired defects, are now increasingly recognized as causes of human diseases. Improvements of our current understanding of alternative splicing regulation may therefore provide opportunities to counter the consequences of mutation. Although many components of the spliceosomal complex have been identified, their roles in splicing regulation (e.g. activator or inhibitor) are not fully understood. We and others have reported the involvement of non-canonical proteins and micro-RNAs (miRNAs) in regulating splicing events, which suggest that this process is controlled by many more factors than previously thought. Hence, constructing a genome-wide map is essential in revealing the mechanisms involved. Identification of such factors and the characterization of ‘ex-vivo’ networks require a system capable of screening a large number of samples. The absence of a generic approach prompted me to develop rapid assay systems based on enzymatic and fluorescence activities (Nasim et al., 2002, 2006, 2008, 2011). Each method comprises two distinct signals either fluorescence or luminescence which can be monitored in mammalian cells, providing a basis for high throughput format.

In this project, we seek to construct a genome-wide map for splicing regulation employing these established approaches and identify novel non-canonical factors including proteins, chemicals and miRNAs that modulate tissue-specific alternative splicing of the human tropomyosin 3 (TPM3) gene. This study will be of substantial use to the study of alternative and aberrant splicing of a wide range of disorders, will greatly enhance the identification of novel drug targets and therapies as well as the development of novel diagnostic tests.

Therapeutic resolution of myodysplastic syndrome (MDS) by inhibition of overactive splicing

Myelodysplastic syndromes (MDS) are the most common adult myeloloid malignancy in the UK and approximately 30% of patients will transform to secondary acute myeloid leukaemia (AML), which has a poor prognosis. There is no cure for MDS and current maintenance therapies were all established prior to the realisation that MDS have substantial genetic components. Hence, there is a need to develop a novel therapy which accounts for the biochemical consequences of such gene defects.

We have previously demonstrated that heterozygous missense mutations in U2AF1 (encoding U2AF35, the 35 kDa component of the heterodimeric U2 auxiliary factor), underlie the majority of MDS. We have demonstrated that these mutations potentiate overactive splicing and alter downstream gene isoform expression and therefore contribute to abnormal haematopoiesis. Our preliminary data indicate that agents that inhibit this overactive splicing may provide beneficial effects in vitro and in vivo mouse models.

The major aim of this project is to develop a targeted chemotherapy for MDS by inhibition of overactive splicing activity of pathogenic nonsense alleles using small molecule agents. In this project we seek to utilise and expand on our preliminary observations to identify small molecule agents capable of targeting U2AF1-mediated splicing defects for selective therapy. Compounds will be identified by means of cell-based and in silico screening and validation will be performed in K562 myeloid cell line models and bone marrow cells derived from MDS patients.

References

  • M. T. Nasim, H. M. Chowdhury and I. C. Eperon. Nucleic Acids Res. 30: e109, 2002
  • M.T. Nasim and R.C. Trembath. Nucleic Acids Res. 33(7): e66 (8 pages), 2005
  • M.T. Nasim and I. C. Eperon. Nature Protocols 1(2):1022-1028, 2006
  • M. T. Nasim, T. K. Chernova, H.M. Chowdhury, B. Yue and I. C. Eperon. Hum Mol Genet. 12:1337-1348, 2003
  • Suraweera A, Lim Y, Woods R, Birrell GW, Nasim T, Becherel OJ, Lavin MF. Hum Mol Genet.(18):3384-96, 2009
  • Katiyar S, Maria A, Covarrubias Y, Casimiro M.C, Zhou J, Jaio X, Hyslop T, Nasim T, Fortina P, Pestell R. Cancer Research; 72(4):1023-34), 2012
  • T. Graubert, D Shen, T. Nasim, D. Link, M. Tomasson, P. Westervelt, J. DiPersio, E. Mardis, T. Ley, R. Wilson, and M. Walter. Nature Genetics 44(1):53-7, 2012
  • M. Brioschi, S. Lento, S. Barcella, M.T. Nasim, S. Ghilardi, S. Barbieri, E. Tremoli and C. Banfi. Data Brief. ; 25;3:117-9, 2015
  • S. Lento, M. Brioschi, S. Barcella, M.T. Nasim, S. Ghilardi, S. Barbieri, E. Tremoli and C. Banfi. J Proteomics.;119:75-89, 2015

Current Projects

  1. Travel Grant (2012-2015) - The Great Britain Sasakawa Foundation
  2. Research Grant (2014-2015) - The Royal Societ
  3. Proof-of-concept Fund (2014-2015) - University of Bradford
  4. PhD Studentship (2014-2017) - The Commonwealth Scholarship Commission
  5. Non Clinical Ph.D Studentship (2016-2019) (With Prof T Palmer)- The British Heart Foundation

Research Collaborations

  1. Dr. Klaus Pors, Institute of Cancer Therapeutics (University of Bradford)
  2. Dr. Steve Shnyder, Institute of Cancer Therapeutics (University of Bradford
  3. Prof. Paul Loadman, Institute of Cancer Therapeutics (University of Bradford)
  4. Prof. Tim Palmer, School of Pharmacy (University of Bradford)
  5. Dr. Colin Wright, School of Pharmacy (University of Bradford)
  6. Prof. Richard Trembath (Queen Marry London, UK)
  7. Prof. N.W. Morrell (Cambridge, UK)
  8. Prof. Ian Eperon (Leicester, UK)
  9. Dr. Lan Zhao and Prof. Martin Wilkins (Imperial College, UK)
  10. Dr. Matt Walter (Washington University, USA)
  11. Dr. Yi-Tao, (Rochester University, USA)
  12. Dr. Christina Bunfii, (IRCCS, Milano, Italy)
  13. Dr. Hao Jiang, (University of Alabama at Birmingham, USA)

Publications

Jing Hu, Alireza Khodadadi-Jamayran, Miaowei Mao, Kushani Shah, Zhenhua Yang, Talat Nasim, Zefeng Wang, and Hao Jiang. AKAP95 regulates splicing through scaffolding RNAs and RNA processing factors.Nature Communications (Accepted). 

M. Brioschi, S. Lento, S. Barcella, M.T. Nasim, S. Ghilardi, S. Barbieri, E. Tremoli and C. Banfi. Data for proteomic analysis of murine cardiomyocytic HL-1 cells treated with siRNA against tissue factorData Brief. ; 25;3:117-9, 2015

S. Lento, M. Brioschi, S. Barcella, M.T. Nasim, S. Ghilardi, S. Barbieri, E. Tremoli and C. Banfi. Proteomics of tissue factor silencing in cardiomyocytic cells reveals a new role for this coagulation factor in splicing machinery control. J Proteomics.;119:75-89, 2015

T. Ogo, H.M. Chowdhury, R. Randall, L. Long, J. Yang, R. Schumerly, N.W. Morrell, R.C. Trembath and M.T. Nasim. Inhibition of the overactive TGFβ signalling by prostacyclin analogues in pulmonary arterial hypertension (PAH). (American Journal of Respiratory Cell and Molecular Biology, Feb 2013) (Impact factor 5.1), 2013

M.A Siddiqui, T. Ogo and M.T. Nasim. Pulmonary Arterial Hypertension: molecular genetic basis and emerging treatments (Invited review). AKMC J 3(2): 30-33, 2012

M.T. Nasim, T. Ogo, H.M. Chowdhury, L. Zhao, C.N. Chen, C. Rhodes, and R.C. Trembath. BMPR-II deficiency elicits anti-apoptotic and pro-proliferative responses through the activation of TGFβ-TAK1-MAPK pathways in PAH. Human Mol Genetics (Impact factor 7.6) (21):2548-58, 2012

T. Graubert, D Shen, Li Ding, T, Okeyo-Owuor, J. Shao, C. Lunn, K. Krysiak, D. Koboldt, D. Larson, M. McLellan, D. Dooling, C. Harris, R. Maupin, R. Fulton, H. Schmidt, J. Kalicki-Veizer, M. O’Laughlin, M. Grillot, S. Heath, T. Nasim, D. Link, M. Tomasson, P. Westervelt, J. DiPersio, E. Mardis, T. Ley, R. Wilson, and M. Walter. Recurrent mutations in the U2AF1 splicing factors in myelodysplastic syndromes. Nature Genetics (Impact factor 35.5) 44(1):53-7(doi 10.1038/ng.1031), 2012

Katiyar S, Maria A, Covarrubias Y, Casimiro M.C, Zhou J, Jaio X, Hyslop T, Nasim T, Fortina P, Pestell R. Mamary gland selective excision of c-jun identifies its role in mRNA splicing Cancer Research (Impact factor 7.8); 72(4):1023-34), 2011

M T. Nasim, T. Ogo, M. Ahmed, R. Randall, H.M. Chowdhury, K. Snape, T. Bradshaw, F. Soubrier, I. Jackson, G. Lord, M. Humbert, N. Morrell, R. C. Trembath and R. Machado,. Molecular genetic characterization of Smad signalling molecules in pulmonary arterial hypertension (PAH). Human Mutation (Impact factor 5.6) 12:1385-89, 2011

Suraweera A, Lim Y, Woods R, Birrell GW, Nasim T, Becherel OJ, Lavin MF. Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation. Hum Mol Genet. (Impact factor 7.6) (18):3384-96, 2009

M.T. Nasim, A.G. Ghouri, B.P. Patel, V. James, N. Rudarakanchana, N. Morrell and R.C. Trembath. Stoichiometric imbalance in the receptor complex contributes to the dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet (Impact factor 7.6) (11):1683-94, 2008

M.T. Nasim and R.C. Trembath. A double reporter assay to determine the efficiency of protein-protein interactions in mammalian cells. Nature Protocols Network, 2007 (DOI: 10.1038/nprot.2007.238)

M.T. Nasim and I. C. Eperon. A double-reporter splicing assay to determine splicing efficiencies in mammalian cells. Nature Protocols (Impact factor 9.9)1(2):1022-1028, 2006

 

In the News/Media

Key genetic mutation in family of blood cancer

New drug target could help PAH patients breathe easier

A dual-light reporter system to determine protein-protein interaction into mammalian cells:

  • Inside Bioassays
  • Oxford Journals
  • University of Leicester bulletin and press release
  • Webbolt, Global Business News, Research and Intelligence
  • The Weekly Lalmonirhat Barta (Bangladesh)
  • Daily Prothom-alo (Bangladesh)
  • The German-Bangla (Deutsche Welle) Radio has broadcasted the invention of dual-reporter system on 26th Dec, 2005

 

 

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