Faculty

Reasearch statement:
Our complex behavioural traits are the end result of a very complex gene regulatory system streamlining developmental and behavioural events of our nervous system. Regulation of gene expression is at the heart of broad as well as fine tuning of development and function of a cell. Transcription factors and regulatory complexes are responsible for bringing about changes in transcription status of cells by responding to extracellular signals- which is fundamental to developmental decisions or behavioural changes upon environmental cues. In many cases these transcriptional changes need to be more stable, leading to long-term or even permanent change in gene expression for a given cell type. This is implemented by permanent modification of accessibility of regions of the genome- by change in chromatin architecture, or epigenetic modifications, such as DNA methylation, post-translational modification of histone tails or remodelling of nucleosome positioning. We use fruit fly (Drosophila) model system to study how change in chromatin architecture is mechanistically associated with developmental and behavioural principles and how their mis-regulations lead to disease pathogenesis. Combining the powerful genetics of Drosophila with recent advances of genomic techniques we will be address questions on how our environment exerts a lasting impact on our brain. Our current questions range from chromatin link of long term memory formation and neuronal activity related changes in genomic accessibility. We will also address how oxidative stress, ageing and memory related brain disorders are causally linked to transcriptional and epigenetic players.

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RecQ helicases are ubiquitious proteins required for maintenance of genome stability. In human, five RecQ family helicases have been identified of which, three are associated with genetic disorders like Bloom Syndrome, Werners syndrome and Rothmund-Thompson syndrome. Out of the five RecQ family helicases, the BLM, WRN and RecQ4 have been extensively studied with respect to DNA binding and unwinding activities. Among the five members of this helicase family, RecQ1 is the least explored helicase in terms of DNA binding and conformational changes associated with DNA recognition and unwinding. RecQ1 is known to unwind variety of substrates like Holliday junctions, forked duplexes and G-quadruplex DNA. Although RecQ1 has not been shown to be associated with any disease, the helicase has vital role in DNA repair and maintaining genome integrity. RecQ1 is the smallest and the most abundant RecQ helicase (72kDa). Diverse studies show that defects in or depletion of RecQ1 impairs cell growth, causes genome instability or induces mitotic catastrophe. RecQ1 is proposed to have a unique role in replication origin firing and nascent DNA synthesis and is critical for replication fork restart. Recently RecQ1 has gained attention due to its role in restoration of stalled replication forks upon DNA damage in association with other DNA repair proteins like PARP1. Our group at IIT Kharagpur is mainly interested in structural and functional characterization of human RecQ1 and understanding the mechanism of unwinding and substrate specificity of human RecQ1 using fluorescence spectroscopic techniques. We are also studying the interactions of human RecQ1 with cellular protein partners that modulate its activity. Apart from human RecQ1 we are also trying to functionally characterize the RecQ helicases from human parasite L.donovani, so as to understand the active DNA repair processes in the parasite that involves RecQ helicases.

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Structural Biology
Prof. Das’s laboratory employs integrated structural biology, combining X-ray crystallography, protein engineering, proteomics, biophysical and biochemical methods to decipher structures and molecular mechanism of important proteins of human pathogens like Mycobacterium tuberculosis and Staphylococcus aureus.
Structure based drug designing
M. tuberculosis is one of the deadliest pathogens known to mankind. Crystal structures of important mycobacterial FAS proteins like high molecular weight ketoacylreductase (HMwFabG), HadAB heterodimeric complex, Protein tyrosine phosphatases A (PtpA), and (3R)-hydroxyacyl-CoA dehydratase (HtdX) have been solved from this laboratory. The structures based inhibitor designing and characterization against PtpA, HMwFabG and HadAB complex showed promises.
Epitope mapping
Mycobacterial Proline-rich secretary antigen (Mtc28) and mammalian cell entry proteins (Mce) and staphylococcal super antigen like proteins (SSL) have importance in host-pathogen interaction and essential for pathogenesis. Crystal structure determination, protein engineering and nanoLC coupled MALDI TOF/TOF based proteomics approaches have been employed for epitope mapping which has implementation in diagnosis and vaccination.
Enzyme Promiscuity and evolution
Probing structural insight into the substrate specificity and road map of evolution are important to address the biochemical property and molecular mechanism of an enzyme. Crystal structures of glycolytic enzymes namely GAPDH, TIM, PGK and PGM are determined to investigate the key sites/residues for biological activity. Analysis of dual specific NADP/IMP phosphatase and promiscuous SaIMPase-II revealed the evolutionary role of active site proximal loops in substrate selection.
Our future efforts will focus on mycobacterial fatty acid metabolism and virulence-associated pathway. The projects will encompass the crystal structure determination and functional characterization of the related proteins towards understanding the mechanism of activity and structure based inhibitor design.

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Penicillin-interactive enzymes (PIEs) include penicillin-binding proteins (PBPs) and beta-lactamases (BLAs). PBPs catalyze the synthesis and remodeling of peptidoglycan (PG). We focus on PG-remodeling enzymes, DD-carboxypeptidases (DD-CPases), encoded by dacA, dacC, dacD and ampH. The characteristic features of DD-CPases are maintaining cell shape and intrinsic beta-lactam resistance, though there are inter and intra species variations in their physiological activities. Therefore, we intend to categorize DD-CPases thoroughly based on their physiological and biochemical functions in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Mycobaterium smegmatis and Mycobaterium tuberculosis. Moreover, we intend to find whether these DD-CPases have any other roles, namely, in evading immunological response, biofilm formation, antibiotic resistance, etc.
As PBPs and BLA share common ancestry, through specific mutational analyses, we aim to know whether their activities are linked and identify the exact point of divergence of these two enzymes. Furthermore, we intend to probe the physiology of BLAs in bacterial cells apart from their roles in cleaving beta-lactams. Various types of BLAs, like TEM1, OXA, ESBL, Metallo-beta lactamases (MBL) and AmpC have a different spectrum of activity. Some of them are intrinsically expressed while the others need induction for proper expression. We are involved in studying the pathway of induction of these enzymes, which can be exploited to design future antimicrobial agents.
We are also involved in identifying the genes related to biofilm formation in E. coli, K. pneumoniae, A. baumannii and M. smegmatis using molecular genetics techniques. Furthermore, we are engaged in characterizing several putative efflux-pump proteins in search of efflux–pump inhibitors for designing combination therapy and intend to correlate biofilm formation with efflux-pump proteins, or BLAs or any other factors, which can lead to multi-drug resistance phenotypes. In addition, we design and validate effective antibiotic combinations and diagnostic tools for BLA detection.

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Viruses are obligate intercellular parasites that rely upon host machinery to perform different steps of their life cycle. Hence, understanding the virus-host interaction in molecular level is essential to develop therapeutic strategies to invade these pathogens. Research in my lab is focused upon understanding the fundamental molecular mechanisms by which RNA viruses assemble their replication machinery to drive viral RNA synthesis and how these viruses utilize host factors to facilitate this process. Viral replication machinery is composed of viral RNA dependent RNA polymerase (RdRp) and genomic RNA template along with the nucleoprotein to form the ribonucleoprotein complex or RNP. RNPs lie ate the heart of the infectious cycle, driving viral gene expression and genome replication during different stages of virus life cycle and interact with a large number of host factors to modulate these processes. Yet, how these macromolecular complexes assemble is largely unknown. We implement biochemical and biophysical and proteomic approaches to understand the molecular interactions between viral and host proteins. Subsequently, information gained from these molecular studies are validated by investigating their physiological relevance during the course of infection. We are also interested in characterizing post-translational modification of viral proteins by host factors and elucidating their role in virus life cycle. Finally, we aim to identify pharmacologically active compounds that can inhibit specific virus-host interaction, hence will have the potential to be developed as antiviral therapy. Currently we are dealing with influenza A and B viruses which causes respiratory infection in human and a wide range of other animals. We are also interested in other viruses that causes human epidemics in Indian subcontinents.

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Dr. Dibyendu Samanta's laboratory focuses on structure-function relationship of membrane proteins, particularly membrane-bound immunoglobulin super-family (IgSF) members and classical cadherins. These IgSFs and cadherins play vital roles in a number of cellular and physiological processes including cell-cell adhesion, immune modulation and host-pathogen interaction. Dr. Samanta's lab aims to understand the detail molecular mechanisms of interactions among IgSF members, and finally modulate these interactions utilizing structure-guided protein engineering approach. Understanding and engineering of these cell surface proteins will provide further insights for the development of novel protein-based therapeutics.

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Research & Development activities of Molecular Genetics & Transgenesis Laboratory can be grouped into three major domains. (A) Metabolic engineering of plants, fungi and algae for qualitative and quantitative improvement of storage-lipids: This program aims to improve the quality and quantity of storage-lipids for edible and biodiesel applications. Genetically modified Brassica juncea and Oryza sativa have been developed for seed-specific expression of transgenes in order to achieve the nutritionally desirable fatty acid profile in mustard oil and rice barn oil, respectively. We are also working on increasing the storage-lipid productivity in these two crops. Our group has isolated few oleaginous fungi including yeasts from plant and rhizosphere, and characterized few critical genes for increasing the lipid productivity. Currently, metabolic engineering of microalgae is being pursued to develop algal strains with enhanced lipid productivity. (B) Functional genomics of rice crop for improved productivity: Our aim is to improve the grain productivity of rice crop. Transgenic rice lines with improved agronomic traits (e.g., semi-dwarfism, tolerance against biotic and abiotic stresses) have been developed. We have generated transgenic rice plants with reduced arsenic and cadmium content in grains. Furthermore, our research group is also involved in genomics-supported screening of aromatic rice cultivars with superior yield-attributing traits to be grown in local agro-climatic zones. (C) Bioprospecting of endophytic microbes for animal health care and plant growth promotion: We are exploring the laboratory-isolated endophytic fungi (obtained from edible plant parts and medicinal plants) for identification of metabolites having bioactive properties such as antimicrobial, quorum sensing inhibitory and antioxidant compounds. We are also working on the genomics and metagenomics of plant associated microbial community to understand the plant growth promoting features of these bacteria and fungi, so as to develop biotechnological strategies for improving the health of animal and plant.

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Neurodegenerative disorders, such as Alzheimer’s disease (AD), Huntington’s disease (HD) and Parkinson’s disease (PD), affect millions of people worldwide. Regardless of numerous attempts to find a treatment approach, therapeutics for these devastating diseases is yet to be discovered. One of the common pathological hallmarks of most age-related neurodegenerative disorders is the accumulation of mutant disease proteins as inclusion bodies. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular protein quality control system. Furthermore, the cellular ability to maintain protein homeostasis declines with age. Therefore the mechanism that restores protein homeostasis either by up-regulating the function of chaperones or enhancing the clearance of mutant disease proteins could be promising therapeutic approach. In my laboratory, we are using HD and AD as a model system to understand the mechanistic basis of impaired protein homeostasis and how that can be restored. We have reported that Ube3a function as a cellular protein quality control ubiquitin ligase and involved in the clearance of misfolded disease proteins (J. Biol. Chem., 2008, 2009 and Neurobiol. Aging,2013). Deficiency of Ube3a in HD mice brain also increased global aggregate load and aggravated HD pathogenesis (Hum. Mol. Genet., 2014). In collaboration with Scientist at IACS, Kolkata, we are also using nanoparticle-based strategy to prevent fibrillation and aggregation of amyloid proteins (ACS Appl. Mat. Inter, 2016, 2017). My laboratory also uses biochemical, cell biological and genetic approaches to understand the physiological function of Ube3a and how its gain as well as loss of function is linked with autism and autism spectrum disorders. We are also screening pharmacological inducers of Ube3a, which might be useful in the therapy of learning and memory disorders.

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My major research activity remains in the field of microbial ecology and environmental biotechnology using both culture independent metagenomic as well as cultured based approaches. Considering a number of natural and impacted ecosystems, a strong research base is created to (i) explore microbial diversity, (ii) elucidate community function in biogeochemical cycle and (iii) develop comprehensive understanding on community?s potential towards developing sustainable remediation/bioprocess strategies. Areas of major focus: (a) Role of indigenous microbial community in mobilization of arsenic in groundwater of Bengal delta plain is elucidated. Metagemic survey coupled with physiological-molecular characterization of bacterial isolates, their whole genome sequencing revealed that release of sediment bound As occurs due to a cascade of microbial processes (facilitating dissolution of host minerals and reduction of As5+ and/or Fe3+). (b) Structural and functional analysis of microbial communities in mine sites and potential for bioremediation. Autochthonous microbial communities within highly hazardous U mine wastes and highly acid, sulphate rich acid mine drainage (AMD) from Cu mine have been explored to understand the communities function and potential role in in situ bioremediation. Massive metagenomic sequencing (NGS) is employed to delineate bacterial/archaebacterial groups potentially involved in (i) generation of acidic solution (ii) in situ precipitation of metals and reduction of sulphate and pH level. (c) Metagenomic analysis of petroleum refinery waste and prospect for in situ bioremediation. Composition and function of microbial communities within petroleum refinery wastes (from Guwahati and Digboi refineries) are studied to develop in situ bioremediation strategies (e) Exploration of the nature and biogeochemical function of deep life residing kilometres below earth surface : Microbial life residing deep under the Deccan basalts is being investigated to gain answer to the fundamental questions related to limits of life and their mechanism of adaptation on earth and potentially analogous extra planetary habitats.

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Dr. Ramkrishna Sen is a Professor in the Department of Biotechnology, IIT Kharagpur. Before joining IIT-Kharagpur, Prof. Sen worked as Assistant Professor in BITS, Pilani for about two years and as Manager (R&D-Biotech) in Cadila Pharmaceuticals for three years. He served as a Fulbright Visiting Faculty in Columbia University, New York, USA. Prof. Sen has been engaged in R&D activities in the areas of Healthcare, Energy, Environment and Water, with a focus on Green Process & Product Development for anticancer biomolecules; Marine bacterial green-surfactants and polymers; Microbial and microalgal biofuels and value added products with concomitant carbon-dioxide sequestration from flue gas and waste valorization in Green Biorefinery models. So far, 19 Ph.D and 36 Masters students received their degrees and 17 Ph.Ds (including two international), 4 PG and 2 UG students are now working under his supervision. He has about 200 publications in international and national journals, books and conference proceedings; and 13 patent applications including one US, one European and one PCT to his credit. Dr. Sen is a member of the editorial board of two international journals. Prof. Sen completed 21 sponsored projects and is currently implementing 6 sponsored projects. He published a book ‘Biosurfactants’ (Springer, USA). Prof. Sen received the following awards/honours: Shastri Indo-Canadian Institute Award (2018); Distinguished Alumni – Jadavpur University (2017); Fulbright Visiting Professor Fellowship (2013–14); Runner-up in National Awards for Technology Innovation in Petrochemicals & Downstream Processing Industries, Government of India (2012) and UKIERI (British Council) Grant for Academic Visits of Universities in London and Northern-Ireland (2007-08). He is the founding member of Global-Biorenewables-Research Society and Biological Engineering Society (India). He is also a life member of IIChE and member of European and Asian Federations of Biotechnology. Prof. Sen administered as Vice-Chairman and Chairman (GATE & JAM), IIT Kharagpur from 2015-2018.

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Computational Structural Biology Laboratory
Reasearch statement:
Macromolecular interactions are essential for different cellular processes in all forms of life, underpinning wide array of biological functions. Structural genomics reveals new molecular complexes with unknown functions. Thus it creates a challenge to computational structural biologists to understand the folding, assembly, evolution, and function of these cellular machines that are governed by the specific interactions of macromolecules. My research aims to elucidate the question What makes the specificity in macromolecular recognition, especially protein-RNA recognition. Our Computational Structural Biology Lab try to address many fundamental questions like how to discriminate the specific and non-specific interactions, what is the role of water molecules in protein-RNA recognition, how protein interaction networks in icosahedral virus capsids assemble to make a spherical like structure that encapsulate and protect viral genome and what makes the specificity of proteins to interact with nucleic acids. We are also interested to understand the structural basis of energetics of folding and binding of RNA with protein. This will contribute knowledge to our understanding of the intrinsically disordered proteins, which undergoes unfolding to folding transition while binding a RNA molecule. Besides, we are developing algorithms for the prediction of miRNA and lncRNA in different plant species. Study of these complex assemblies is not only important for their functional role but also they serve as major therapeutic targets, and such a study should be relevant to both basic science and pharmacology.

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Drug resistance is a major threat to our healthcare system and is a worldwide problem. Widespread use of antibiotics and drugs has resulted in cells acquiring resistance and they are often resistant to multiple drugs (e.g., multidrug resistant S. aureus, TB). Drug resistance is also observed in cancer where some cancer cells can survive anticancer treatments. Our aim is to understand the processes that generate resistance in great detail because this would help us design better treatment strategies. A second interest of the lab is to understand causes of phenotypic plasticity in isogenic populations. Genetically identical individuals in identical environment were thought to have identical phenotype (e.g., drug resistance). However, that is not the case. It has been known for quite some time now that a small number of cells in a microbial population can tolerate and survive very high drug concentrations. These cells are known as persisters. With the advent of single cell techniques, it is becoming even more clear that isogenic cells can and do show significant phenotypic differences. However, the causes of such differences in phenotype or the cellular processes that generate these differences are not well understood. A third aim of the lab is to connect phenotypic plasticity with long term evolution – how short term phenotypic variations (e.g., persistence) can influence long-term evolution of drug resistance. We use bacteria and yeast as model systems for our work. In addition to basic microbiology and molecular biology techniques, we use FACS, microscopy, high throughput sequencing and mathematical modeling to understand these processes better.

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My present research interest lies in understanding the role of specific nutrients like vitamin in immune system. We would determine how the nutrients affect the adaptive immune system by regulating the development of T helper cells. T helper cells play important role in protecting us from various pathogens by producing cytokines. However, if unregulated the immune responses generated by T helper cells can cause various inflammatory disorders. Based on the cytokines in the microenvironment and produced and the expression of transcription factors, T helper cells have been classified into distinct subsets. Among different vitamins, role of vitamin A and vitamin D have been explored in the differentiation of certain T helper cells. In addition, the function of these vitamins have also been explored in disease models like allergic asthma and experimental autoimmune encephalomyelitis. We would like to define how vitamin A and D regulate the development of various T helper cells including IL-9-producing Th9 cells. Th9 cells play important role in the development of asthma, exacerbate ulcerative colitis; while they aid in the expulsion of helminthic infection and antitumor activity in mouse model of melanoma. Thus, delineating the role of vitamin A and vitamin D in regulating the differentiation of Th9 cells will aid us developing future therapeutics. We would like to build a network of inflammatory diseases whereby IL-9 play key role. We are also intersted in understanding the role of the Hox family of transcription factors in the differentiation of T helper cells.

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Molecular Immunology & Cellular Microbiology Laboratory
In context of the Indian sub-continent, Tuberculosis and Visceral Leishmaniasis are dreadful infectious diseases caused by Mycobacterium tuberculosis and Leishmania donovani respectively. The advent of extreme drug resistance has aggravated the situation. The search for newer molecular targets as well as alternative therapeutic strategies is clearly evident.
Using CRISPR/Cas9 mediated genome editing our lab tries to have a thorough understanding of the host factors governing parasite pathogenesis. We are looking into the roles of phosphatases and kinases in mediating parasite survival. Biochemical assays are being set-up for the functional characterization of macrophage factors phosphorylated by mycobacteria secreted virulence factors. Functional characterization and adaptive resistance mechanism studies are carried out for an essential Leishmania enzyme. Besides, the role of host factors that enable controlled phagosome maturation allowing efficient promastigote to amastigote differentiation as well as factors dampening macrophage proliferation but promoting amastigote proliferation would be studied.
We are also trying to envisage into host-directed immunomodulatory therapeutics against mycobacterial and leishmania infection that would overcome the pathogen-induced classical macrophage activation block and thereby re-enable them to kill the parasite. Drug repurposing approaches against a Leishmania specific essential enzyme using tri-cyclic anti-depressants are also being carried out whose application through the creation of reticulo-endothelial blockade would be tried out. We are also engaged in developing a rapid, low-cost, point-of-care diagnostic kit for extreme drug resistant TB.

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Structural Biology & Protein Engineering Laboratory
Biophysics, Biochemistry; Enzymology; Signal Transduction and Gene Expression; Protein engineering; Nuclear Magnetic Resonance (NMR) Spectroscopy. The overarching research goal of Dr. Soumya De's laboratory is to decipher the structural and dynamic principles that govern protein functions and their regulation. This is achieved using solution NMR spectroscopy and other biophysical methods. Regulation of HOX transcription Factors: Transcription factors play central role in many biological processes that range from cell cycle progression to cell differentiation and organism development. Hence, it is not surprising that the functions of these proteins are under tight regulation and their disruption lead to several diseases raging from developmental disorders to cancer. Regulatory mechanisms of these proteins include post-translational modifications, protein partnerships and DNA-binding autoinhibition. We are investigating the molecular basis of function, regulation and specificity of HOX transcription factors. We are focussing on Drosophila and Human HOX factors. The Drosophila HOX factors have well-defined biological roles and are ideal systems to explore the molecular basis of their function and regulation. The Human HOX factors, on the other hand, are important therapeutic targets for cancer treatment.

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Our lab has been working on Entamoeba histolytica, a unicellular, anaerobic protozoan parasite that causes amebiasis or amebic dysentery in humans. The life cycle of Entamoeba is biphasic and consists of the motile trophozoite form and the non-motile cyst form. Infection occurs by the ingestion of mature cysts of this organism. Encystation is a complex process marked by the formation of the chromatoid body, glycogen granule, and formation of four nuclei and deposition of a chitin wall. However, there is a relative lack of data on the mechanisms that control the transition between trophozoite and cyst forms. The primary aim of our lab is to understand the regulation of gene expression and unravel the components of signal transduction pathways during encystation. Entamoeba invadens, a reptilian parasite, is used as a model organism because of its ability to undergo encystation under in vitro conditions. We are also interested in various aspects like nuclear division, stress-related cell signaling pathways (MAPK and AMPK pathways), the role of nucleotide sugar transporter in chitin synthesis during encystation. The other major project in the lab concerns the screening and characterization of several surface antigens for the development of potential diagnostic markers and identification of potential vaccine candidates, and the identification of new drug targets and understanding the mechanism of activation of metronidazole, the prodrug. His other ongoing research activities are the development of marker free Pod borer resistant Chick pea and Pigeon Pea trough transgenic approach. His group is also involved in the evaluation of the applicability of a dominant nuclear male sterility system in rice for hybrid seed production in collaboration with National Rice Research Institute, Cuttack. Dr. Ghosh is also involves in nanoparticle based drug delivery in cancer cell and characterization of photoactivable anticancer drug in collaboration with Department of Chemistry.

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