Mechanism and Regulation of Nuclear Expansion:
Our group is addressing two major questions in nuclear expansion using Tetrahymena thermophila as a model organism.
1) Mechanism of nuclear expansion
The nucleus is a membrane-bound organelle that undergoes dramatic changes in size and shape during cell cycle progression. One such change is fragmentation of the nuclear envelope (NE) during mitosis. This fragmentation is a specific feature of metazoans. In yeast, for example, a "closed" mitosis without NE fragmentation requires nuclear membrane expansion to allow chromosome separation within a single intact nucleus. A more general change is the expansion of the NE in post-mitotic cells to accommodate chromatin de-condensation and DNA replication. Nuclear remodeling is a complex process requiring coordinated biosynthesis, targeting and interaction of the nuclear membrane with nuclear pores, inner nuclear membrane proteins and chromatin. How this is accomplished is not clearly understood in any system.
We use Tetrahymena thermophila as a model system to study nuclear remodeling. The unicellular, free-swimming ciliate undergoes closed mitosis, as does yeast. A striking advantage of Tetrahymena is that, nuclear envelope expansion in this organism occurs to a dramatic extent (~10-15 folds) during specific stages in cell conjugation; a process that can be highly synchronized in cell cultures. We have recently discovered that dynamin related protein 6 (Drp6) is required for nuclear remodeling in Tetrahymena. However, the mechanism by which Drp6 performs its function is not known. Therefore, one important objective is to understand the mechanism of Drp6 function in nuclear remodeling.
2) Cell cycle regulation of lipid homeostasis and membrane biogenesis
Nuclear expansion is a regulated process that occurs at a particular stage of cell cycle. A phosphatidic acid phosphatase (PAH1) regulates nuclear expansion in yeast by undergoing phosphorylation and dephosphorylation. While phosphorylated form of PAH1 is involved in nuclear expansion, its dephosphorylated form inhibits the process. The phosphorylation and dephosphorylation state of PAH1 is regulated by cell cycle related kinase (Cdk1) and phosphatase (Nem1 and Spo7 complex) respectively. We have established the role of large PAH1 homologue in lipid homeostasis and maintaining ER tubular structure in Tetrahymena and observed functional conservation with yeast homologue. However, the regulation of PAH1 is not known in Tetrahymena. We found three Nem1 homologues and would address their role in regulation of nuclear expansion, lipid homeostasis and ER structure. Since we did not find any homologue of SPO7 in Tetrahymena, we would also try to identify the protein performing the similar function in this organism.
The contemporary distribution of biota within the Indian subcontinent must have been shaped by its unique history. The Indian subcontinent was part of Gondwanaland and had close tectonic associations with Africa, Madagascar and Seychelles before eventually colliding with Eurasia, resulting in the orogenesis of the Himalayas. The initial contact of the Indian plate with Southeast Asia may have potentially resulted in exchange of biota across these two landmasses. On the other hand, the contemporary Indian subregion reusers insular from other biogeographic zones areas owing to various geographic barriers. Prolonged insularity generally promotes diversification in lineages with limited dispersal ability, resulting in endemic radiations. Beyond bearing these unique spatial and temporal signatures in its biotic assembly, the Indian subcontinent itself is heterogeneous in its topography with about ten major river systems/ basins flowing out of the peninsula. Additionally, the Indian subcontinent has about six major hill ranges. Cumulatively, these factors would have had (or still have) a significant effect on the contemporary distribution of biota within the Indian subcontinent, resulting in an interesting mix of lineages. Indian biota may therefore be composed of ancient Gondwanan relicts to lineages that dispersed more recently from other regions. I am personally interested in South Asian herpetofauna (reptiles and amphibians), largely owing to their diversity and antiquity. However, in my lab we have a set of broad interests ranging from understanding systematics, biogeographic patterns and evolution of characters in a diverse range of taxa from the Indian subcontinent. As a lab PI, I want to usertain and inculcate a keen interest in organismal biology, ecology, natural history, systematics and biogeography.
Host-pathogen interactions, cell signalling events, immunopathogenesis of infection, cancer microenvironment, molecular events in cancer metastasis and apoptosis.
With the shifting demographics towards older age, there is a major concern for age-related disorders. 90% of individuals dying each year are due to age-related causes. Understanding the genome, epigenome and proteome between healthy and diseased state of these individuals pave a way for unravelling bio-markers for early diagnosis and/or therapeutics for various diseases. Our goal is to find these underlying players that change the micro-environmental niche differently in a diseased state during the developmental process of aging and hence are responsible for these age related-disorders. We are currently focusing on understanding the pathomechanism of two neurodegenerative eye disorders (Glaucoma, the leading cause of irreversible World Blindness and Corneal Endothelial Dystrophies) as well as Cancer using a pleothora of cellular, biochemical, genetics, genomics and molecular biology techniques involving human samples, Drosophila models as well as in vitro cell lines.
Studies on antibiotic resistance and virulence in gram negative bacteria
Signaling Systems in Plants, Light perception, flowering time control, circadian rhythm and biological clock.
Agricultural Biotechnology
The following two broad problems are currently being pursued in the lab using a combination of in vitro reconstitution, cell-based experiments, advance fluorescence microscopy/spectroscopy, computational and micro-manipulation tools:
1) We are interested in understanding the interplay of cellular membrane parameters and the kinetics of aggregation of intrinsically disordered proteins (IDPs) such as Amyloid-beta, full-length human Tau and alpha-Synuclein. This will help us understand how different IDPs and host cellular membranes influence each other in terms of aggregation kinetics of the IDP or the changes in the physico-chemical parameters of the cellular membranes that might eventually drive neuronal membrane deformation resulting in neurodegeneration and propagation of amyloids from cell to cell.
2) Mechanism by which Mycobacterial secretory components manipulate host cellular membranes to evade phagosome maturation.
Trillions of microbes (bacteria, viruses, fungi, and parasites) reside on various surfaces (mucosa, skin, etc.). An ideal system of mutualism as long as both parties (host and microbes) are happy and benefit. Any perturbation (antibiotic treatment, altered diets, body clock, dark-light balance, diseases, etc.) can endanger the host's health. The questions are: a) How is balance maintained (do we need a holistic understanding of body energy balance, endocrine dynamics, and gut-brain communication) and b) to achieve the required balance, do we need all those whopping amounts of microbes (overtly bacteria, to be precise gut bacteria as that is the largest in number and gut is the major reservoir).
My lab currently tries to understand a) various ways to induce gut bacterial dysbiosis and its consequence on the gut-adipose-brain axis and b) the role of the gut microbiome (bacteria) in various diseases (diabetes, obesity, NAFLD, and PD).
We work with animals (mice models, Th1 and Th2, and soon with select Knock Outs), humans, and tissue organoids (gut epithelium, spheroids, and perhaps soon with some brain organoids). The lab also uses various bioinformatic tools to map the microbiome on the host metabolome. The Aichlab utilizes regression-based data science methodologies of AI-ML and uni- and multivariate statistics, clustering, classification, and grouping of similar and dissimilar datasets, and network-based mathematical modeling of lab-generated data in metabolism, metagenomics, cell biology, immunology, microbiology, and neuroscience.
My lab also attracted Industry funding to establish methodologies to predict microbiome from the host metabolic profile. The people in the lab get a flavor of both academia and industry environment and training. I encourage young researchers to develop skills to be an entrepreneur.
With this funding, AichLab developed a novel Gut Function Test (GFT). The GFT predicted gut microbiome via blood metabolites. The first in the world. GFT eliminated the need to collect fecal material to identify gut microbiomes. We got CDSCO approval, and the Indian Patent was granted. The funding led to translate into a spin-off named MicrobioTx. MicrobioTx also designs personal probiotics based on the GFT report.
Our work is being widely cited by the media. A few to mention are OnlyMyHealth, BioSpectrum, Nuffoodsspectrum, DBT-ILS, Nextedge, ANI, NEWSVOIR.
Evolution of the work that I initiated @ NISER. My primary goal is to establish an effective way to strengthen innate mucosal immunity. The modern-day world requires more work than play. At the same time, such demand puts us under various stressors (cause of stress) with the potential to perturb homeostasis. By homeostasis, I try to imply a process where, physiologically, we try to restore normalcy by adjusting the parameters of several physiological functions of a system. To begin with, a few of the lab's interests were a) how we achieve the restoration and b) how balancing acts are performed among different physiological events, such as immunity and metabolism. My research group developed methodologies to quantify the psychological stress status of individuals, correlating stress with disease susceptibility (e.g., metabolic syndromes and infectious diseases) and how we can prime innate immunity to prevent such infections. To prime immunity, we selected probiotics and host defense peptides. We also tried to enhance the efficacy of these immune modulators with nano-materials. The initial leads from our work prompted me to understand the gut microbiome's role on the gut-adipose-brain axis. This approach is critical in understanding health and physiology to establish intrinsic intervention for the host.
My focus is on understanding the role of the gut microbiota in modulating innate immunity and metabolism. We try to understand the effects of the gut microbiome on the brain and the effects of psychological stress (as a perturbation to brain function) on the gut microbiota. We try to understand the reversibility of the Microbiome-Gut-adipose-Brain axis. The study is being done in differentially immune-biased mice models. Human studies are also being planned with Industry sponsorship. We are also developing different organoids (mini-organ). The gut epithelium organoid of mouse origin is already established in the laboratory. We are now initiating adipose and brain organoids.
We also analyze existing data to correlate metabolome and gut microbiome in various human metabolic disorders to develop personalized probiotics using bioinformatic and clinical studies.
Hundreds of trillions (1014) of tiny creatures call our body home, including bacteria, viruses, fungi, and others. They're not always bad news; our health depends on having a thriving collection of microbes. Our results show that the correlation between individuals' genomic and metagenomic (especially for gut microbiota) features might lead to a better understanding of physiology and better sustenance of health. There are microbes everywhere in our bodies. Some coat our skin (yes, even after washing our hands). Others populate the inside of our mouth (some forming tooth-destroying plaque, and others that are harmless or beneficial). According to some estimates, our large intestine is the largest repository of microbes - about three pounds' worth. If we could count the number of individual bacterial cells, we would find that they vastly outnumber our human cells, although they are small.
Some details are fuzzy, but we know that our microbiomes are linked to our health. The immune system doesn't develop properly without signals from skin microbes. Microbes can influence obesity and have been linked to various inflammatory and autoimmune disorders like rheumatoid arthritis. Our health is connected with the health of our tiny passengers, but scientists are still struggling to understand what a "healthy" microbiome should look like.
We know, for example, that people whose gut ecosystems are overrun by deadly Clostridium difficile can be cured with microbes from a healthy donor - the now-famous fecal transplant. We know probiotics can prevent a horrific infection called NEC (Necrotizing enterocolitis) that kills preemies. Beyond that, results are mostly inconclusive. Probiotics protect against diarrhea in some trials but not others, for example.
While microbes seem important in ascertaining health, understanding the mode of action and mechanisms is unclear. It has been shown that food plays an essential role in setting up the microbiome in the gut, but how the change in diet will alter the microbiome and how it will influence health is an important area yet to be explored.
When our food reaches the microbes in our large intestine, the starch, sugar, fats, and proteins are digested and absorbed. This process leaves a handful of nutrients called "prebiotics." They include a variety of carbohydrates that our enzymes can't digest, including soluble fiber, resistant starch, and specific oligosaccharides. Likely, many of the beneficial effects of fiber and a diet rich in fruits and vegetables may be because of such a diet's effects on gut microbes.
There's no doubt that people will dope via microbes. Companies are talking about significant cosmetic changes. There will be new smells and new functions. It's an exciting area because you don't have to modify a person's genes to give them a new role. You can provide them with a pill with a microbe that has a unique function. If the microbes don't stay around, you might have to take that pill every day, but you could still add a living, bio-producing organism into your system that could last longer or do different things than a typical drug.
The central question of my research group is, how does microbiota maintain homeostasis to define health? By perturbing a typical microbial environment, we would like to know (a) how the restoration dynamics, (b) how the perturbation affects physiology (e.g., metabolism and innate mucosal immunity), (c) how the gut-adipose-brain axis regulates the gut microbiome or how is physiology being regulated by the microbiome.
We use immunologically (Th1- and Th2) differently biased mice models. We have initiated human studies to compare metabolic and neuronal diseases with gut microbial dynamics. We have also developed mouse intestinal epithelial organoid systems. We plan to extend the work to establish a) adipose organoids to understand the browning of white adipose tissue and b) a combination organoid system of Mouse Intestinal Organoid (MIO), Enteric Nervous System (ENS) cellular components, and Vagal Sensory Neurons. Eventually, we will plan to perform organoid studies with human systems.
More focused information on specific research topics that are ongoing in AichLab
Microbes, diet, and them: You are what you eat is a common anecdote. Thus, diet is important in modulating gut microbiomes. To understand the impact of diet-induced microbial dysbiosis on host physiology, we used two strains of conventionally immune-biased mice in our study. We treated young adult (6-8-week-old), male C57BL/6 (Th1 biased) and BALB/c (Th2 biased) mice with diets rich in either non-resistant starch or unsaturated fat or saturated fat for four or eight weeks, along with strain and time-matched controls. Results revealed the differential impact of the diets on intestinal microbes and metabolic parameters like host adiposity, glycemic index, and meta-inflammatory status. We found the starch-rich diet could revert pathogenicity associated with the metabolic parameters after eight weeks in both mice strains. We correlated this alleviation in pathogenicity to the enhancement in a) microbial diversity and b) the abundance in the phyla Verrucomicrobia following eight weeks of dietary intervention. We observed opposite trends in fat-rich diet-treated mice where the diet-induced pathogenicity could be corroborated with abundance in microbial phyla Proteobacteria and Epsilonbacteraeota, coupled with a reduction in Bacteroidetes. The extent of both the physiological changes and microbial influences were specific to mouse strain and duration of treatment. Following these observations in vivo, we conducted in vitro studies to understand the direct interactions between adipose tissue microenvironment resident cell types. Further, we treated matured adipocytes with select microbes to evaluate their anti-adipogenic potential. This study was initiated by Dr. Raktim Mukherjee, a PhD candidate at AichLab. A few titbits can be found here.
Gut microbial dysbiosis & consequences: One major role of the microbiome in maintaining health. Thus, dysbiosis disrupts the home to cause diseases. Therefore, it is important to have a balance of beneficial microbes to avoid disruption. But the question is, how do the microbes do it? A key paradigm is to perturb the microbiome and study to establish the role of the microbiome (collection of all commensal microbes, such as bacteria, fungi, viruses, and their genes) in maintaining health. This project used Dextran sulfate sodium (DSS) to perturb the gut microbiota in Th1 and Th2-biased mice.
The current study revealed that the dysbiotic condition was stable and long and greatly impacted immune dysregulation following treatment with DSS. Moreover, the DSS-treated group of both mice strains showed typical diseased symptoms resembling human colitis pathophysiology. The current study with DSS treatment also helped us establish a new model system for studying colitis. The current study utilized a multi-omics approach to understand colitis's onset and etiology. Further studies are ongoing to understand the mechanism. This study was initiated by Ms. Sohini Mukhopadhyay, a Ph.D. candidate in AichLab. A few relevant publications from this research can be found here.
Altered Light-dark cycle: The light and darkness affect physiology in various ways. The circadian clock is one such vital parameter. The circadian clock can coordinate, regulate, and predict physiology and behavior in response to the standard light-dark (LD) cycle. If we alter the LD cycle, it can perturb behavior, the brain, and associated physiological parameters and the commensal microbiome. The extreme alteration of LD can be done by exposing ethically approved animal models (in this case, mice) in constant darkness (DD) or light. We studied the role of DD for an extended period on male and female mice of Th1 (C57BL/6) and Th2(BALB/c) biased mice. The length of DD exposure and the sex of experimental animals are crucial variables that could alter the impact of DD on the brain, behavior, and physiology, which have not yet been explored. We exposed mice to DD for three and five weeks and studied their impact on 1) behavior, 2) hormones, 3) the prefrontal cortex, and 4) metabolites in male and female mice. We also studied the effect of three weeks of standard light-dark cycle restoration after five weeks of DD on the above-mentioned parameters. The results revealed DD exposure was associated with anxiety-like behavior, increased corticosterone, pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), downregulated neurotrophins (BDNF and NGF), and altered metabolite profile during DD exposure is dependent on the sex of the animals and immunological bias. Females showed a more robust adaptation than males under DD exposure. The work was primarily developed by another PhD candidate Mr. Dhyanendra Singh. More detailed reports can be found here.
Longitudinal analysis of gut microbial and immune development: The gut microbial profile is dynamic. The composition (abundance and diversity) changes spatially and temporally during development and growth. While the consequence of the dynamicity is imaginable and reprehensible, but to be grasped yet confidently. The Aich lab tries to understand the longitudinal dynamic behavior of gut microbiota in neonatal till pre-pubescent (post-natal day 1 till day 28) C57BL/6 mice. Preliminary results established a significant shift in gut microbial structural and functional composition from postnatal day 14 onwards. The gut microbial shift also established a robust age-dependent association with the intestinal mucosal barrier formation postnatal day 14 ahead. Studies further showed a postnatal age-related impact of gut microbiota perturbation, with a gradual increase in the relative abundance of Proteobacteria and a reduction in Bacteroidetes and Firmicutes. We found significant barrier integrity disruption, reduced TJPs and IECs marker expression, and increased systemic inflammation at P14D of AVNM-treated mice. Moreover, the microbiota transplantation showed recolonization of Verrucomicrobia, proving a causal role in barrier functions. Our investigation revealed P14D as a critical period for neonatal intestinal development, regulated by specific microbiota composition. We continue the study with the gut epithelium organoid model developed in AichLab by Mr. Uday Pandey (a graduate student). A master's student, Ms. Srishti Shah, is now involved in the project. Some relevant information can be found here and on social media.
Direct and indirect assault: While working on various perturbation and developmental models, we also thought of developing a comparative analysis following direct and indirect perturbation of the gut microbiome. We have already briefly discussed DSS-induced perturbation developed by Sohini. Dr. Pratikshya Ray, a former Ph.D. candidate of the lab, studied the role of various antibiotics (Vancomycin, Ampicillin, Neomycin, Ciprofloxacin, AVNM) on gut microbial dysbiosis and its effects on host physiology. Ms. Swati Sagarika Panda (another Ph.D. candidate) is studying the role of a much broader antibiotic cocktail (we call it a 9-antibiotic cocktail or, in short, 9-AB) on host physiology following a gut microbial perturbation in mice models. Preliminary studies suggested a key impact on the brain and adipogenesis. This adipogenesis is being further studied by master's students, Ms. Shivani Meena, Ms. Isha Dwivedi, and Ms. Akanskshya Nayak, in vitro in 2D- and 3D adipocytes. A comparative direct and indirect assault (perturbation) of the gut microbiome was initiated by Sohini and was assisted by an MSc project student, Debopriya Saha. Currently, Mr. Kartika Sahu is analyzing those data further using various networking and phase space models.
Microbes, Mitochondria, and their roles in NAFLD and PD: A new venture initiated by the trinity of new Ph.D. candidates Arka Jyoti De, Tanuja Mohanty, and Ankita Das. Ankita also plans to develop a few brain organoids and some integrated MSc project students.
Another iMSc project student, Sunaina, was pursuing an association study in Pan Omics. Dr. Sangita Mitra, a PDF in the lab also get a shot at it during her stint in the lab.
Pre-NISER research
Ph.D. (Supervisor: Professor Dipak Dasgupta). I explored mechanisms of interactions of select antitumor antibiotics with DNA and the role of magnesium ions.
I moved to Stockholm, Sweden [Stockholm University (SU) and Karolinska Institutet] (KI), following the submission of my Ph.D. thesis, to start my 1st PDF Research (Supervisor: Professor Astrid Gräslund, SU) career. My study area aimed to understand higher-ordered DNA structures (by 2D NMR, CD, and other biophysical techniques). Around the same time, I also got introduced to the area of Fluorescence Correlation Spectroscopy (FCS) to understand base pair dynamics in nucleic acids, including PNA, at a single-molecule level with Professor Rudolf Rigler (Rulle, KI). We built the world's first FCS to work in the ultraviolet light region. In Rulle's lab, I also got trained in fixing and maintaining an Argon ion laser and a dye laser.
I moved to the University of Saskatchewan (Saskatoon, SK, Canada) for the 2nd PDF position. I preferred the Canadian PDF over other opportunities at Louis Pasteur Institute (Strasbourg, France) or the USA. At Saskatoon [University of Saskatchewan] for my PDF (Supervisor: Professor Jeremy Lee) research, I started working on establishing a higher-ordered DNA structure in vivo using c-myc and c-src oncogenes.
While working on the project, we discovered a novel form of DNA that could conduct electricity when doped with specific transition metal ions. We term this form of DNA as M-DNA [M-stands for 'metal'], and we patented it. We also tried to develop an abzyme against M-DNA. A company named ADNAVANCE was founded. I got so hooked up with the discovery of M-DNA that I declined offers from the Dana Farber Cancer Institute (Harvard University, Boston). I also turned down a job offer from a start-up photonics company in Boston.
I joined a biopharmaceutical company in Canada after my PDF training as a Group Leader [Bio-imaging]. After a year, I accepted a position at the University of Saskatchewan, as in charge of the Biophysical section of Saskatchewan Structural Sciences Center, Saskatoon, SK, Canada. Shortly, I was offered a position at VIDO (now VIDO-Intervac) as a scientist (PI at the level of Assistant Professor) to work in Omics to understand innate mucosal immunity. At VIDO, I developed several programs in innate mucosal immunity to understand the effects of psychological stress on host-pathogen interactions for bovine enteric and respiratory diseases in cattle models and enhance the efficacy of immune stimulators using immune stimulators nanotechnology in chicken.
I continued at VIDO from 2002 to 2009. In 2006, I got promoted to the next level, i.e., equivalent to Associate Professor. During this time, I got associated with a) the Department of Biochemistry and b) the Department of Physiology and Anatomy of the University of Saskatchewan, Saskatoon, Canada, as an Adjunct Professor and Associate faculty member. As an Adjunct professor or associate faculty member, I designed courses on Systems Biology and Physiological Genomics to teach 4th-year undergraduate students.
In 2009, we returned to India. When I left VIDO, I had seven ongoing projects funded by various Canadian Funding Agencies. I could not bring these funds, for obvious reasons, to India. I then transferred those projects to other faculty members of VIDO.
In 2009, I joined NISER as an Associate Professor and started understanding the effects of psychological stress on humans to develop programs on innate mucosal immunity
The fundamental difference between prokaryotic and eukaryotic translation initiation is that the former uses Shine-Dalgarno (SD) sequence on the mRNA to recruit small ribosome subunit and locate AUG codon or rarely GUC, CUC or UUG codon as a translation start site, while the latter uses eIF4F complex to bind mRNA and locate AUG codon or rarely CUG, UUG or GUC as a start codon by 5` to 3` scanning mechanism. Some of the examples listed below shows the involvement of non-AUG codon as a translation start signal.
In Saccharomyces cerevisiae, GRS1 encodes two isoforms of Glycyl-tRNA synthetases, one initiates from upstream in-frame UUG codon (encoding signal sequence for mitochondrial import) while the regular cytoplasmic version initiates from downstream AUG codon. For the synthesis of Alanine t-RNA synthetase (ALA1) protein a consecutive ACG ACG codon are utilized as an alternate translation start site. It has been reported recently that MHC class-I molecule can load antigenic precursor which is synthesized by using CUG as an initiation codon recognized by leucine tRNA and non-conventional eIF2A translation initiation factor. A genome wide ribosomal profiling analysis of vivo translation study reported that translation initiation from upstream non-AUG codon is widespread in S. cerevisiae under starvation condition. However, the importance and the basic mechanism for these initiations are still unclear. A number of yeast mutants have been identified that are able to initiate at the non-AUG codons. These mutants were designated as Sui— (Suppressor of initiation) phenotypes. Sui— phenotypes are novel mutations that causes break down of AUG codon selection fidelity. Thus, Sui— mutants provide an important tool to understand the molecular mechanism of non-AUG codon selection.
The focus of our lab is to understand the molecular mechanism of non-canonical translation initiation processes in Saccharomyces cerevisiae using molecular genetic techniques.
The key questions are as follows:
Neural circuits and behavior, Neuroendocrine regulation
What I cannot create, I do not understand
- Richard Feynman
So is true for Life. For nearly a century, it was believed that Humans and its close relatives such as yeast and other eukaryotes were the sole owners of the Cytoskeleton, a mechanical framework that supports cells and carries almost all essential process within. However, recent discoveries have proved this to be a myth and shown us that the cytoskeleton was an innovation of our distant ancestors - 'Bacteria'. The bacterial cytoskeleton provides the most simplistic framework to understand the mechanical basis of all cellular process such as spatial organization and compartmentalization, cell shape establishment, cell movement, DNA segregation and cell division that are vital to the propogation of life. One of the most fascinating aspects of the cytoskeleton is their remarkable ability to self-organize and assemble into a great diversity of dynamic structures.
Broadly, our research interests lie in evolution of self-organisation, form and function in biological systems and in understanding the means by which bacterial pathogens have exploited this organization in pathogenesis for their survival and reproduction. In our research laboratory, we aim to understand how tiny cells such as bacteria achieve cellular organization and how the mechanical properties of their cytoskeleton allow them to perform the cellular functions.
We pursue these research interests through studying the following process in life:
• Cell division and Spatial organization in Bacteria - Bacterial cytoskeleton dynamics, Cytokinetic ring assembly, Regulation of cell division control and anti-bacterials targeting bacterial cytoskeleton.
• Bacterial Metabolism & Biofilms - Molecular pathways by which Bacterial proteases regulate lipid metabolism & biofilm formation.
• Bacterial Pathogenesis - Molecular Mechanisms of Bacterial effectors that target and affect Eukaryotic Cytoskeleton and Cell Cycle.
• Synthetic Biology - Synthetic Protein Polymers: Evolution of synthetic cytomotive proteins for use in biological & artificial cell systems.
Given the rapid increase in the rate of multi-drug resistance, there is a resurgence of the once conquered infectious diseases. There is an urgent need for a new class of antibiotics and bacterial cell division has proved to be an attractive target. Thus we are currently actively focused on regulation of cell division and spatial organization in bacteria. We also have an ongoing effort on creating "synthetic cytomotive proteins" for use in artificial cells.
Evolutionary Ecology Lab (EEL@NISER)
I am an evolutionary ecologist interested in understanding the forces and mechanisms that shape an organism's evolutionary trajectory. Rapidly changing anthropogenic stressors introduce novel selection pressures, leading to biodiversity loss and the emergence of new coping mechanisms in certain species. The biotic interactions among communities, populations, and individual organisms are central to this adaptation, which drives evolutionary processes. Modern sequencing techniques have shown that these interactions extend beyond the macroscopic world, significantly influencing microbial communities as well. At the intersection of these realms, macroscopic hosts and their associated microbes interact, shaping each other's evolutionary paths.
My research aims to trace these biotic interactions at various organizational levels, from host communities to individual hosts, host-microbiome interactions, and microbial communities, to understand their impact on organismal evolution. By employing classical eco-evolutionary approaches and utilizing both wild and laboratory-reared insect populations as model systems, my lab is interested in uncovering how organisms adapt to novel and rapidly changing selection pressures.
Project 1: Impact of anthropogenic noise on biodiversity and ecosystem health - estimating the threat and potential coping mechanisms
The health and sustainability of an ecosystem depend on its biotic organisation. A diverse ecosystem is a good indicator of its health, as biodiversity provides resilience and redundancies that are key to ecosystem functioning. Hence, threats to biodiversity, in the form of human activities, can lead to the functional collapse of an ecosystem. Unfortunately, most research on biodiversity is patchy, intrusive, biased towards charismatic taxa, and often overlooks elusive and nocturnal species. Since over 50% of organisms, including diurnals, rely on acoustics for communication, passive recording can provide an efficient, non-invasive, yet less biased estimate of biodiversity. However, acoustic communication suffers from an omnipresent, pervasive threat, anthropogenic noise.
Most organisms use acoustics for conspecific recognition, competition, and mate choice. This communication has evolved under conspecific and heterospecific masking (signal overlap) giving rise to coping mechanisms like spatial, temporal, spectral (pitch) separation of signallers, and selective hearing in receivers. Anthropogenic noise, which has no particular signal structure, can act as a novel selection pressure by altering the complexity of masking, rendering the existing coping mechanisms ineffective. This can lead to a communication breakdown and large-scale loss of species diversity.
We aim to understand how acoustically communicating communities cope under such pervasive anthropogenic stress. Since insects are the most diverse yet understudied taxa, we aim to use their diversity as an indicator of ecosystem health. Among insects, Ensiferans (crickets and katydids) are one such taxa that are present across a variety of habitats and have mesmerising acoustic diversity and complexity. Unfortunately, these insects are poorly studied, with almost no data on their diversity and distribution along eastern India. We aim to study the impact of anthropogenic noise on their diversity, communication patterns, and potential coping mechanisms to ascertain the threat level in these habitats.
Structural biology of soluble and transmembrane proteins, and De novo design of proteins.
Proteins are workhorses of a cell, engaged in a wide range of tasks comprising structural stability, cell signaling, catalysis, transporting, molecular printing, membrane fusion, regulation, etc. Understanding the mechanism that underlies the functioning of these molecular gadgets is an intriguing question, and defines the fundamentals of biological processes. This is an interdisciplinary research program as we set out to address the question using X-ray crystallographic methods coupled with biophysical, biochemical and computational approaches.
Our structural biology group aim to deduce the structure based mechanism for the functioning of cation selective channels from viruses. The structures not only enhance our current knowledge, but also provide leading point for the structure based drug design. Also, we are interested in the structural biology of bacterial two component systems, a wide spread signal transducers.
Our other research program is de novo protein design, which aim to put our understanding of principles that define protein folding and functioning into test. Here, we seek to design scaffolds that are tailored to have predetermined non-covalent interactions as well as functions.
Cellular and Immunological investigation towards altered host cell responses
The fundamental consequences of cellular responses associated to altered physiological processes during infection, cancer and/or tumor progression, inflammation and immunogenic responses in various cases of altered host cell functions and phenotypes are the prime interest of our ongoing research.
We have been working in the field of host cell responses and cellular immunology with special interest of ongoing immune-regulatory responses, cellular function and phenotypes associated to Cell mediated immunity (CMI) of T cells and accessory antigen presenting cells. Currently, we have major interest groups within NISER and also with external collaboration, where we are investigating functional expression of Toll like receptor (TLR) and Transient Receptor Potential Vanilloid (TRPV) Channels in cell mediated immunity (CMI), analyzing cellular and immunological response(s) of host cells during experimental Chikungunya virus (CHIKV) infection along with anti-cancer immunity as major projects.
In brief, our research focuses to dissect out the important roles of cellular and immunological aspects to decipher the cellular pathways, strategies associated to altered host cell responses for an ongoing infection, tumor progression, inflammation-immunity and immuno-regulatory processes associated to diseases biology in different contexts of cellular responses. Research with cell lines, primary cells, animal model and also with the human blood samples from normal donors and patients with due consents and National guide lines are the prime components for such experimental studies. Such understanding will be helpful towards designing immuno-therapeutic strategies to control various diseases.
Our research focusses on-
1. Elucidating pathophysiological mechanisms of neurological disorders focusing on ion channels.
2. Creating novel brain models using human induced pluripotent stem cells (hiPSCs) from patients
to study neurological disorders.
3. Translating novel mechanisms to develop therapy against neurological diseases.
List of Publications
Google scholar link- https://scholar.google.com/citations?user=xsEnuCEAAAAJ&hl=en
My research interest is to understand structure-function relationship of viral proteins in viral entry, genome replication and packaging into capsids.
Cell-entry of alphaviruses: Chikungunya virus, an aedes mosquito-transmitted alphavirus, enters cells through receptor-mediated endocytosis, and membrane fusion in acidic pH of endosome. Two viral surface proteins, E1 and E2 facilitate entry process. E1 'pulls' apposing endosomal and cell membranes close enough, after endosome acidification, so that they fuse and open a pore. My lab is interested in understanding the acidic-pH triggering mechanism for E1 and structural changes in the protein that lead to membrane fusion.
Nucleic acid packaging in dsDNA viruses: Viruses with double stranded DNA genome pack DNA into capsids at very high densities. Some bacteriophages Human herpesviruses (one of those with large genomes) pack their genome into pre-formed capsid through concerted action of a portal complex and terminase complex. Terminase complex of herpesviruses can be a good drug-target. My lab studies structure-function relationship of terminase protein complex components to explain the mechanism of action of the complex.
Replication complexes of flaviviruses: another interest in the lab is on replication complexes of flaviviruses. Dengue virus, a member of the virus family, forms a complex of more than five different proteins (nsp1,2a, 2b, 3, 4a, 4b and 5) formed from a single polyprotein through proteolytic processing. Special membrane-bound replication complexes are formed from ER membrane surface and viral RNA is amplified inside these vesicles. We aim to characterize these complexes and study interactions amongst the proteins in complex.
Rational drug discovery and development require a streamlined interdisciplinary effort from researchers working in a specialized area. From active collaboration, the drug discovery process can be and has been significantly shortened by addressing bottlenecks in drug discovery (off-target effects, polypharmacology, and chemoresistance). Our research focuses on some unaddressed questions that could contribute to chemotherapy.
Establishing the bioactivity of a lead molecule (of any origin) from an in vitro study is the start of a long journey in the drug discovery pipeline. The pharmacological effect of the lead molecule observed in vitro may not directly correlate with the in vivo results due to the molecule's physicochemical properties, bio-pharmacokinetics, or structural mimicry. Here, we try to design suitable study models (in silico, in vitro, and/or in vivo) that can progressively help develop a reliable formulation.
The following are the areas and related publications we presently focus on:
