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Basic Research in Modern Biology – achievements
Cell and Molecular Biology

Studies conducted on elucidating the role of signalling pathways involving C3G in cellular plasticity have led to the identification of a novel cellular regulator that specifically interacts with and inhibits the activity of oncogenic Bcr-Abl, but not that of cellular Abl kinase. The results have also shown elevated expression of TC48 and activation of the endogenous expression can inhibit proliferation and enhance therapeutic response of CML cells.

Work conducted to study the regulation of sister chromatid recombination by ATM and ATR kinases has shown the role of both ATM as well as ATR in regulating homologous recombination (HR). However, only ATR was shown to suppress long-tract gene conversion associated with HR. The data obtained for the first time show that ATM and ATR distinctly regulate sister chromatid recombination during DNA double-strand break repair.

Research being conducted on expression and trafficking of cell surface adhesion molecules and their contribution to endometrial receptivity have led to the identification of the cell surface protein repertoires of endometrial epithelial cell lines which may be of relevance in embryo-endometrial adhesion. These studies have also revealed the role of Rab Coupling Protein (RCP) in the trafficking of integrin alpha v to the cell surface of endometrial epithelium.

Study initiated on role of FtsH Protease in Escherichia coli cell division have for the first time revealed, the role of the essential protease FtsH, in bacterial cell division. Since FtsH protease is present in many pathogenic bacteria, besides playing an essential role in the regulation of cell division the protease could in future be developed into a potential antibacterial target.

Studies carried out on Type II phosphatidylinositol phosphate kinase function have led to the discovery of new class of enzymes that regulates cellular communication system, that are important in the context of many diseases such as Type II diabetes mellitus and in future may lead to the discovery of novel therapeutic strategy.

Research on elucidating spatio-temporal regulation between cohesin and chromatin in executing faithful chromosome segregation during meiotic cell cycle has shown the role of kinetochore in pairing of homologous chromosomes and chromosome condensation, which are the key processes for the faithful chromosome segregation.

Research work carried to understand the molecular functions of E2F1 in a tumour microenvironment in the X15-my concomouse model of hepatocellular carcinoma have established the dual role of transcription factor E2F1 in tumourigenesis. E2F1 facilitated cellular proliferation by stimulating genes involved in cell cycle control and replication during early stages of hepatocarcinogenesis. However, during late stages, E2F1 triggered replicational stress-induced DNA damage and sensitised cells to apoptotic death in a p53-independent manner.

Biochemistry and Biophysics

Studies on Vibrio Cholerae cytolysin has provided insights into the mode of action of Vibrio Cholerae cytolysin (VCC), which is considered as a prominent model toxin in the family of bacterial β-barrel pore-forming toxin. The study indicates a novel mode of regulatory mechanism imposed by a lectin activity site within the VCC toxin. Further work is being carried out to explore the details of the structural basis of such regulatory mechanism(s) in the context of the mode of action of the VCC toxin.

The group working on elucidating the role of MAP kinase directed phosphatases in Toll like receptor signalling mediated protective Th 1 type immunity have for the first time identified that tumor necrosis factor receptor-associated factor (TRAF)3, a negative regulator of TLR pathway plays a critical role in the establishment of visceral infection.

Representative images showing the expression pattern of satellite 3 transcripts (pink color speckles) in the nucleus (blue color) of HeLa cells upon exposure to heat shock or other forms of physiological stressors as indicated.
Representative images showing the expression pattern of satellite 3 transcripts (pink color speckles) in the nucleus (blue color) of HeLa cells upon exposure to heat shock or other forms of physiological stressors as indicated.

Research work being carried out to understand the role of different domains on the stability of interferon-γ induced human guanylate binding protein has led to the identification of a novel DxEKGD motif in hGBP1. The truncated and mutant proteins showed that both the alpha helix of the intermediate region and the motif plays critical role in the stimulation of the activity which may be related with antiviral activity of the protein.

Research work being carried out to unravel the role of human non-coding satellite-III transcripts in cellular stress response have shown novel role for a long non-coding RNA in transcriptional silencing. The study has demonstrated that Satellite 3 transcripts are essential for the human cells to mount heat shock response and that the cell do not survive if these transcripts are knocked down. Further they have also shown that the Satellite 3 transcripts suppress transcriptional activity during heat shock by recruiting transcription factors.

Cancer Biology

Group working on simultaneous inhibition of plasminogen system along with matrix metalloproteinase in controlling angiogenesis have newly synthesised phthalazine compound and platinum-azo compound which can be used as small molecule inhibitor. Isoquinilone another compound synthesised by the same group could be used as imaging molecules for cancer cells.

Studies carried out on characterisation of functional interaction between estrogen receptor and ETS transcription factor in breast cancer cells have revealed a positive co-relative expression of ESE1 with ERα in breast cancer patients and showed poor patient survival. It is also shown that ESE1 expression may lead to ER-negative breast cancer phenotype. Further work is being carried out to determine binding regions of these two proteins to design a peptide which can prevent their interaction.

Microbiology

Studies on iron uptake mechanism in Mycobacteria has demonstrated for the first time a new pathway for iron acquisition in M.tuberculosis which would be important in understanding the mechanism of bacterial survival during TB. Using protein chemistry, molecular biology and microscopy techniques it is shown that human holo-transferrin interacts with GAPDH both in vivo and in vitro

TEM image demonstrating the binding of transferrin-gold particles on the   surface of M.tuberculosis H37Ra.
TEM image demonstrating the binding of transferrin-gold particles on the
surface of M.tuberculosis H37Ra.
Co-immunoprecipitation experiments indicate that transferrin specifically interacts with and M.tb GAPDH present in the cell wall fraction of M.tuberculosis H37Rv. Cell wall fractions of M.tuberculosis were incubated with biotinylatedhuman holo-transferrin, interacting proteins were captured by streptavidin paramagnetic particles. Western blot analysis was done with α-GAPDH antibody.

Study conducted on Molecular characterisation of DacD (a putative DD-carboxypeptidase) of Escherichia coli have for the first time revealed the biochemical property of DacD through in vitro biochemical analyses which is supported by in silico studies. In vitro characterisation of DacD is indeed a major step towards understanding how three homologous proteins (PBP5, PBP6 and DacD) are involved in exerting different or partially overlapping cellular activity at different time points of various growth phases.

Cellular and Molecular Immunology

Work on Notch activated signaling cascades and the consequences for T-cell homeostasis have shown that Notch activity – characterised by interactions in the cytoplasm of cells – is critical for T-regulatory cell survival and likely an important regulator of its function.

Study being conducted to understand the molecular events involved in inhibition of DC activation/maturation by HGF has demonstrated the molecular basis for HGF-induced DC inhibition and provides the first evidence for an involvement of Btk in proximal signaling events induced by HGF.

Research work to elucidate the role of Apoptosis-inducing factor (Aif) in T lymphocyte development have shown that aif- hypomorphic harlequin (Hq) mice show thymic hypocellularity and a cell- autonomous thymocyte developmental block associated with apoptosis at the ß-selection stage, independent of T cell receptor-ß (TCRß) recombination. These data indicate that Aif, a ubiquitous protein, serves a lineage-specific non-redundant anti-apoptotic role in the T cell lineage by regulating ROS during thymic ß-selection.

Structure Biology and Chemical Biology

Work on Morpholino-based antisense-synthesis and its application has successfully developed methods for making modified Morpholino-based antisense and has also shown successful application in cancer cells.

S. typhimurium methyl citrate synthase decamer structure
S. typhimurium methyl citrate synthase decamer structure

Identified the role of β‟ motif in geminivirus replication. The work has revealed that conserved residues in Rep that probably form a loop / β -hairpin structure interacts with ssDNA while residues in the β‟ motif located outside the loop are involved in coupling ATP induced conformational change to DNA binding.

High resolution X-ray crystal structures of two enzymes, Salmonella typhimurium 2-methylcitrate synthase (2-MCS) and acetate kinase (StAckA) has been determined. These enzymes have provided the basis for understanding the molecular basis for the specificity of the enzymes towards substrates and plausible mechanism of catalysis.

Vascular Biology

Investigation being carried out to elucidate signalling mechanism of sFRP4 mediated inhibition of angiogenesis has shown for the first time that secreted frizzled related protein 4 (sFRP4) can inhibit angiogenesis both in-vivo and in vitro conditions. The excessive leakiness of endothelial monolayer is coupled with increased ROS levels that promote the endothelial cells to undergo apoptosis.