Dr. Talat Nasim,

Associate Professor

Research

Current PhD projects:

1. Therapeutic resolution of BMPR2-mediated signalling defects in pulmonary arterial hypertension (PAH)

2. Therapeutic resolution of pulmonary arterial hypertension (PAH) by natural products

3. Re-purposing established drugs for the resolution of pulmonary arterial hypertension (PAH)

4. Development of a personalized therapy for pulmonary arterial hypertension (PAH)

5. Therapeutic resolution of coronavirus (COVID-19) diseases by natural products

6. Therapeutic resolution of Myelodysplastic Syndrome (MDS) by natural products

Apply for one of our PhD projects - Postgraduate - University of Bradford

Potential funding sources are:

Faculty for the Future Fellowship

EMBO Fellowships

Royal Society Newton International Fellowship

Human Science Frontier Programme

Marie Curie Individual Fellowships

Commonwealth Scholarship Commission (https://cscuk.fcdo.gov.uk/about-us/scholarships/)

My key research interests are as follows:

1. Investigation of BMP and TGFb 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 TGFb 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 TGFb signalling and/or promote the BMP signalling may provide protection in PAH. We identified some small molecule agents that restore the balance between the TGFb 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-TGFb 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 A number of ‘leads’ have been identified through a medicinal chemistry programme (unpublished data).The major objectives of this part of research are to investigate (a) the molecular mechanisms by which the TGFb signalling is activated in PAH, and (b) therapeutic resolution of PAH by chemical agents including natural products and established drugs that restore the balance between BMP and TGFb 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.

H.M. Chowdhury, M. A. Sidiqui, S. Kanneganti, N. Sharmin and M. T. Nasim*. Hum Mol Genet.27: 373-384, 2018

H.M. Chowdhury, N. Sharmin, M. Baran, L. Long, N.W. Morrell, R. C. Trembath andM. T. Nasim*.Hum Mol Genet Feb 2019

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).

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

There are more than 3000 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.

M. T. Nasim, S. Jaenecke, A. Belduz, H. Kollmus, L. Flohe and J.E.G. McCarthy; J. Biol. Chem. 275: 14646-14852, 2000.

3. Modulation ofSplicing in human diseasesIdentification ofnon-canonical factors regulating tissue-specific alternative splicing

Mutations in pre-mRNA splicing signalsaccount for both inherited and acquired defects, are now increasinglyrecognized as causes of human diseases. Improvements of our currentunderstanding of alternative splicing regulation may therefore provideopportunities to counter the consequences of mutation. Although many componentsof the spliceosomal complex have been identified, their roles in splicingregulation (e.g. activator or inhibitor) are not fully understood. We andothers have reported the involvement of non-canonical proteins and micro-RNAs(miRNAs) in regulating splicing events, which suggest that this process iscontrolled by many more factors than previously thought. Hence, constructing agenome-wide map is essential in revealing the mechanisms involved. Identificationof such factors and the characterization of ‘ex-vivo’ networks require a systemcapable of screening a large number of samples. The absence of a genericapproach prompted me to develop rapid assay systems based on enzymatic andfluorescence activities (Nasim et al., 2002, 2006, 2008, 2011). Each methodcomprises two distinct signals either fluorescence or luminescence which can bemonitored in mammalian cells, providing a basis for high throughput format. In this project, we seek to constructa genome-wide map for splicing regulation employing these established approachesand identify novel non-canonical factors including proteins, chemicals andmiRNAs that modulate tissue-specific alternative splicing of the human tropomyosin3 (TPM3) gene. This study will be of substantial use to the study ofalternative and aberrant splicing of a wide range of disorders, will greatlyenhance the identification of novel drug targets and therapies as well as thedevelopment of novel diagnostic tests.

4. Therapeuticresolution of myelodysplastic syndrome (MDS) by modulation of aberrant splicingMyelodysplasticsyndromes (MDS) are the most common adult myeloloid malignancy in the UK and approximately 30% of patients willtransform to secondary acute myeloid leukaemia (AML), which has a poorprognosis. There is no cure for MDS and current maintenance therapies were allestablished prior to the realisation that MDS have substantial geneticcomponents. Hence, there is a need to develop a novel therapy which accountsfor the biochemical consequences of such gene defects. We have previouslydemonstrated that heterozygous missense mutations in U2AF1 (encoding U2AF35, the 35 kDacomponent of the heterodimeric U2 auxiliary factor), underlie the majority of MDS. We have demonstrated that thesemutations potentiate overactive splicing and alter downstream gene isoformexpression and therefore contribute to abnormal haematopoiesis. Our preliminarydata indicate that agents that inhibit this overactive splicing may providebeneficial effects in vitro and in vivo mouse models. The major aim of thisproject is to develop a targeted chemotherapy for MDS by inhibition ofoveractive splicing activity of pathogenic nonsense alleles using smallmolecule agents. In this project we seek to utilise and expand on ourpreliminary observations to identify small molecule agents capable of targetingU2AF1-mediated splicing defects for selective therapy. Compounds will beidentified by means of cell-based and insilico screening and validation will be performed in K562 myeloid cell linemodels 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. NucleicAcids Res. 33(7): e66 (8 pages), 2005.

M.T. Nasim and I. C. Eperon. NatureProtocols 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, BirrellGW, Nasim T, Becherel OJ, Lavin MF. Hum MolGenet.(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

5. 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.

Current Research Collaborations:

Dr. Klaus Pors, Institute of Cancer Therapeutics (University of Bradford)

Dr. Steve Shnyder, Institute of Cancer Therapeutics (University of Bradford

Prof. Paul Loadman, Institute of Cancer Therapeutics (University of Bradford)

Prof. Tim Palmer, School of Pharmacy (University of Bradford)

Prof. Colin Wright, School of Pharmacy (University of Bradford)

Prof. Richard Trembath (Queen Marry London, UK)

Prof. N.W. Morrell (Cambridge, UK)

Prof. Ian Eperon (Leicester, UK)

Prof. Lan Zhao and Prof. Martin Wilkins (Imperial College, UK)

Prof.. Matt Walter (Washington University, USA)

Dr. Yi-Tao, (Rochester University, USA)

Dr. Christina Bunfii, (IRCCS, Milano, Italy)

Dr. Hao Jiang, (University of Alabama at Birmingham, USA)

Research collaborators

Contract researchers