The Centre will carry out and promote multi-disciplinary innovative research in biotech sciences. Contemporary research at the interface of disciplines with integration of science, engineering and medicine and emphasis on the relevance to the regional societies is being undertaken. Broad range of areas synergizing with biotech science will be pursued:
Biomedical Science is a continually changing and dynamic subject and is therefore enormously challenging and involves analyses of life processes to gain an understanding of health and the methods for diagnosing, analyzing and treating diseases. Areas within the above domains being currently initiated include analyses of complex diseases for identification of intervention points and development of knowledge-based drug discovery approaches. Application of the principles of engineering and natural sciences to tissues, cells and molecules could be described as Bioengineering and is closely linked with modern biotechnology. It advances knowledge from the molecular to the organ systems level and aids in the development of innovative biologics, materials, devices and informatics approaches for prevention, diagnosis and treatment of disease as well as improvement of crops and quality of the biosphere. Nanoscience for biotechnology, wherein the emphasis would be on design of nov el nano-devices for bio-sensing, diagnostic and therapeutic utility would be among the priority areas. Biochemical and Biophysical studies at the molecular and cellular level and as part of systems biology foster progress in comprehending the mechanisms underlying the control of cellular physiological processes and the consequences of its perturbation. Climate change, agriculture and environment are interrelated processes taking place on a global scale. Integration of climate models with design strategies for transgenic crops and environmental impact of climate change using mathematical as well as physical approaches are also being envisioned to be priority areas. A major aspect of biotech revolution concerns addressing regulatory and IPR issues as well as policy analyses. The inter-relationship of policy & IPR exists along with every aspect of biology and therefore this domain will grow synergistically along with other multidisciplinary areas.
Specific research themes currently being pursued:
Understanding the physiological processes of self-nonself discrimination in terms of physicochemical principles of molecular interactions has been a major focus of our research. Our work on the pluripotency of primary immune response led to discovering new ways of antibody degeneracy and has impacted the evolving paradigm shift in immune recognition and generation of antibody repertoire [Immunity (2006) 24:359]. We have analyzed how immune system reacts when encountered with the antigens that keep changing shape and showed that the restricted paratope conformational repertoire on binding of an antigen to multiple independent antibodies may be relevant for minimizing possibility of selfreactive antibodies. Molecular insights into the functional mimicry in the context of immune response were addressed using structural, immunological and thermodynamic approaches. We have demonstrated how paratope plasticity facilitates molecular mimicry of otherwise unrelated antigens. While our analyses of carbohydrate-peptide mimicry provided important conceptual leads towards design and development of new generation of vaccines, the analyses involving carbohydrate-porphyrin mimicry provided possible mechanistic understanding of the molecular pathology of porphyria. Structural issues pertaining to innate immunity and food allergies are also being addressed.
Principal Investigator: Dr. Dinakar M Salunke
Our Disease Biology Laboratory is currently focused on understanding the molecular mechanisms associated with the pathogenesis of debilitating clinical events such as thrombosis, ischemia, infarction, strokes and heart attack that cause significant morbidity and mortality in many disease conditions including hemolytic disorders. Studies including our recent works suggest that the activation of pro-thrombotic/ -inflammatory/ - coagulation factors in circulation and their interaction with cell surface ligands and proteins contribute significantly to the blockage of blood vessels causing thrombosis, strokes and heart attack in these patients. Our works show that the plasma glycoprotein von Willebrand factor (VWF) that normally serves the hemostatic functions (blood clot formation to stop bleeding during injury) is significantly hyper-reactive in promoting thrombosis and coagulation events in hemolytic disease. We also show that the extracellular hemoglobin (released due to intravascular hemolysis) interacts with VWF and promotes the mechanisms of thrombosis. Besides, understanding the crucial interaction between different molecules, factors, proteins and ligands associated with the development of pathogenesis of thrombosis, strokes, infarction and cardiovascular events in hemolytic disorders, we are also focused on finding the gene variations and SNPs associated with the above complications.
Our research interest is also concentrated understanding the hypoxia regulation of some transcription factors and coagulation factors, and their association with hyper-coagulation and thrombosis. Also to understand that any variation in these hypoxia-regulated genes have any adaptive advantage against these clinical complications in the high-altitude living people.
Our laboratory is also focused on understanding the molecular pathogenesis of thrombosis, coagulation and thrombocytopenia in microbial infections.
Our studies are also designed to understand the pathogenesis of injury and trauma; specifically listening to crosstalk of the molecules associated with intravascular hemolysis, thrombosis, coagulation and inflammation in trauma.
Principal Investigator: Dr. Prasenjit Guchhait
The blueprint of life is resident in the genome of every organism. For all cellular processes to function optimally, the integrity of the genome has to be maintained. Conversely, plasticity in the genome can relieve selection pressure imposed by an adverse environment. These two conflicting requirements have led to the presence of molecules and pathways that either prevent or facilitate changes in the genome. The antagonistic action of these two different sets of molecules probably ensures that genomic plasticity is calibrated to endow adaptive capability without severely compromising genetic viability. We aim to unearth the mechanism utilized by these molecular throttles of evolution to achieve function. These studies will provide valuable insights into how organisms evolve and adapt to the environment.
The biological processes under scrutiny in the laboratory currently are (i) Stress- Induced mutagenesis (ii) Stress- induced epigenetic modifications (iii) Transposition (iv) Mechanism and fidelity of replication of the RNA genome of the Japanese Encephalitis Virus (JEV) (v) Nucleotide Excision Repair (vi) DNA Mismatch Repair (vii) Regulation of recombination frequency. The first three processes are responsible to enhancing phenotypic diversity to allow presentation of multiple phenotypes for natural selection and thus drastically heighten the probability of adaptation. The last three processes ensure that the integrity of the information resident within the genome is maintained. The fourth process- replication of the JEV genome- may be accurate and error-prone during different stages of genome duplication.
Using X-ray crystallography as the primary tool in conjunction with relevant biochemical methods and allied biophysical techniques, we aim to provide structural insight into the mechanism of action of enzymes/enzyme-complexes that are critical in each of these processes. Through ongoing and new collaborative efforts, we aim to shed more light on the relation between biochemical and structural properties of these enzymes and their observed and predicted roles in physiology. A clear mechanistic understanding of the activity of these molecules will provide deep insight into how these molecules impact the ability of an organism to survive and propagate in diverse environments. About 155 years ago, Darwin had postulated that new species arise through natural selection of genetic variations. Through studies on molecules that influence the appearance of these variations, we aim to contribute towards developing a deeper and more fundamental understanding of how organisms evolve and adapt.
Principal Investigator: Dr. Deepak T. Nair
Our research group is interested in illuminating the fundamental molecular mechanisms regulating cell division and intercellular communication, with the larger aim of elucidating their underlying impact on important biological processes.
Mammalian cells divide with a high degree of fidelity, ensured through tight molecular regulation of multiple pathways, to generate two daughter cells that contain the correct diploid complement of chromosomes. Elucidation of the molecular mechanisms of mitotic regulation is imperative to understand the basis for asymmetric stem cell division leading to differentiation, for understanding early development of multicellular organisms, as well as for potential therapeutic intervention in major diseases, prominently cancer and polycystic kidney disease.
We are studying molecular events controlling the metaphase to anaphase cell cycle transition, monitored by the Spindle Assembly Checkpoint, and dissecting the role of the ubiquitous molecular motor, cytoplasmic dynein, in regulating this process. We are also exploring molecular control of cytokinesis, the terminal step of mitosis, to understand the role of both molecular motors and vesicular traffic in ensuring completion of cell division.
Independently, we are probing the molecular basis for biogenesis and function of tunneling nanotubes - thin, tubular cytoplasmic connections between cells - a relatively newly discovered mode of intercellular communication seen in several eukaryotes. These structures play important roles in various physiological processes underlying health and disease, but the molecular mechanisms controlling their formation and function remain largely unresolved.
Our approach to answering the above questions is multi-pronged. We employ cell biological studies, high-resolution optical microscopy, biochemistry, proteomics, biophysical and structural biological approaches. In the future, we will collaboratively extend our studies to one or more model organisms, to understand the influence of intracellular molecular crosstalk in shaping the development and physiology of an organism.
Principal Investigator: Dr. Sivaram V S Mylavarapu
Our research group is working in the area of Bio-nanotechnology including Nanotechnology and Cancer Biology. We will be using interdisciplinary approach including synthetic chemistry, cancer biology, pharmacology, and bioinformatics. Our research interests include drug delivery, gene therapy, combination therapy for cancer therapy and exploiting the nucleo-cytoplasmic communications to find new targets for cancer nanomedicine.
Nanomedicine: Engineering of hybrid nanoparticles for effective, targeted, and controlled drug/gene delivery is one of the major challenges for successful cancer therapy. The design of new materials to overcome the existing limitations of delivery vehicles, and to target multiple pathways is required for successful cancer therapy.
Our research groups focuses on engineering of different nanomaterials based on liposomes, polymer, dendrimers and nanoparticles as effective drug delivery systems for cancer therapy. One of the major challenges in cancer therapy is the lack of universal drug delivery systems, as cure for cancer depends strongly upon the genetic background of the cancer cells. We are exploiting how the genetic background of the cancer affects the drug delivery systems in cancer therapy.
As various cellular signaling pathways regulate the cell proliferation, invasion, and metastasis of cancer cells, it is challenging to develop cellular toxicity by cutting down only one of the pathway. Therefore, the combination therapy and especially the combination of chemotherapy and gene therapy can be one of the strategies to cut down the multiple cellular pathways for effective cancer therapy. We are developing nanomaterials comprising drug delivery and DNA/siRNA delivery vehicles that would transform the cancer therapy by increasing efficacy of cutting down multiple pathways.
Cancer Biology: The understanding of nucleo-cytoplasmic communications in cancer cells is required for development and engineering of effective cancer therapies. Therefore, we are exploiting these communications in colon, lung, and breast cancer models to understand the common targets in different tissue specific tumors. We would be using different genomic, metabolomic and proteomic approaches to discover different molecular targets for cancer therapy in tissue specific tumors.
Principal Investigator: Dr. Avinash Bajaj
Many bacteria assemble multitude of surface proteins and assemblies like pili to adhere to biotic and abiotic surfaces. This bacterial adherence is a key step for bacterial colonization, pathogenesis, and even for beneficial effects to the host and environment. The structural biology of Gram-positive bacterial pili is an emerging area of research, while much progress has been made in Gram-negative bacterial pili. Pili of Gram-negative bacteria are composed of non-covalently assembled protein subunits (pilins), for example, chaperon/usher assembled pili, type IV pili, curli pili. In contrast, the pili in Gram-positive bacteria are made of covalently linked pilins with the help of cysteine proteases called sortases. The presence of pilus gene clusters that encode pilins and related proteins have been identified in several Gram-positive organisms. Certain unique structural features possibly dictate the diversity in their cellular targets and the resulting infections or beneficial effects distinguish these organisms and their pilus type from one another. Our lab works on bacterial cell surface adhesins with focus on pilus-like structures in Gram-positive pathogenic and non-pathogenic organisms towards understanding their architecture and assembly, and their role in adherence and biofilm formation.
Principal Investigator: Dr. K Vengadesan
Protein metabolism is essential for normal cellular function and involves both synthesis and degradation of proteins on a constant basis. Eukaryotic cells are equipped with three different systems to accomplish protein degradation: mitochondrial proteases, which degrade the majority of mitochondrial proteins, lysosomes, which degrade membrane and endocytosed proteins, and the ubiquitin-proteasome system, which degrades the vast majority of long and short-lived normal and abnormal intracellular proteins. In fact, up to 80-90% of all intracellular proteins are degraded via the ubiquitin-proteasome system, which is considered to be the major pathway of intracellular protein degradation. A wide variety of biological processes are controlled by the reversible, post-translational modification of proteins, which is a covalent attachment of ubiquitin, a highly conserved 76-residue polypeptide. Like protein phosphorylation, the ubiquitin-proteasome system is a dynamic and reversible process, involving enzymes that add ubiquitin (E1 activating enzymes, E2 conjugating enzymes and E3 ligases) and enzymes that remove ubiquitin (deubiquitinating enzymes or DUBs).
The main focus of our laboratory is to understand the ubiquitin-proteasome signaling system, which regulates different cellular process like cell cycle progression, proliferation, differentiation, transcriptional activation and signal transduction. Besides normal function, the ubiquitin proteasome system (USP) contributes to several pathological states of clinical disorder including inflammation, neurological disorder and cancer by altering the function of activating, conjugating, ligating and deubiqutinating enzymes. Understanding the molecular basis for function of ubiquitin pathway enzymes will provide a better understanding of ubiquitin signaling system and helps in therapeutic intervention of UPS related diseases. Our approach studying the ubiquitin proteasome system is based on the combined application of biochemistry, biophysics, structural biology, mass spectrometry-based proteomics and chemical biology.
Principal Investigator: Dr. Tushar K Maiti
Research in my lab is broadly directed at understanding the key events that cause inflammation during infection and autoimmune disorders. Uncontrolled inflammation contributes to the pathogenesis of inflammatory diseases as well as the development of cancers. We use Salmonella in cell culture and mouse system with the key objective to understand molecular mechanism underlying the observed inflammation.
The gram negative, facultative intracellular bacterial pathogen Salmonella is one of the most frequent causes of acute gastroenteritis in humans. The disease results from a complex cascade of interactions between the pathogenic bacterium, the host intestinal epithelium, the commensal microbiota and the immune system of the host. The disease manifestation is characterized histologically by massive infiltration of neutrophils (PMN), a phenotype also observed in some of the chronic recurrent inflammatory disorders with unknown etiology such as Crohn's disease (CD) and ulcerative colitis (UC).
Our recent paradigm shifting discovery, demonstrating host-caspase-3 mediated processing of Salmonella virulence proteins, has opened several new exciting avenues in biology of infectious diseases. Using state of the art tools of microbiology, molecular biology and fluorescent-imaging we envisage to carry out host-pathogen interaction studies. The ultimate goal is not only to combat bacterial pathogenesis but also find therapeutic solutions to auto-immune disorders.
Principal Investigator: Dr. Chittur V Sirkanth
The vertebrate skeletal muscle is crucial to locomotion, posture, and metabolism among other functions. The adult skeletal muscle is made up of muscle fibers (myofibers), connective tissue (connective tissue and connective tissue fibroblasts) and the muscle stem cells (satellite cells). The myofibers are elongated, multinucleate cells that are the contractile units of the skeletal muscle, formed during development by fusion of myoblasts. The connective tissue connects the muscles to tendon and bone, forms an important component of the niche within which the myofibers and muscle stem cells reside and transmits the force of muscle contraction. The satellite cells are quiescent stem cells which are activated during muscle injury or disease and are crucial to muscle regeneration. Previously, our work on the mammalian skeletal muscle connective tissue fibroblasts identified the Wnt/beta-Catenin pathway transcription factor Tcf4 as the first marker for these fibroblasts and using mouse genetic experiments and in vitro co-cultures that Tcf4 and the muscle connective tissue fibroblasts are crucial for proper muscle maturation, differentiation and function.
The skeletal muscle fibers have distinct metabolic and contractile properties based on their function and location. Myofibers can be 'slow' (slow contracting, utilizing oxidative metabolism and slow to fatigue) or 'fast' (fast contracting, utilizing glycolytic metabolism and quick to fatigue). Muscles that are postural or are used for longer periods of time are generally rich in slow fibers whereas muscles that are used for short periods of time but require fast contraction are rich in fast fibers. Muscle fiber type is quite plastic and based on usage, fiber type in adults can convert from one to another. Skeletal muscle myosin heavy chains (MyHC) are the proteins that confer fiber type specific contractile properties to myofibers. There are mainly 6 MyHCs: MyHCI (slow), MyHCIIa, MyHCIIx/d, MyHCIIb (fast), MyHCembryonic and MyHCneonatal. MyHCIIa, MyHCIIx/d and MyHCIIb are expressed from neonatal stages and in the adult, MyHCI is expressed during development, neonatal stages and in the adult while MyHCembryonic and MyHCneonatal are normally expressed only during development and transiently during muscle injury or disease in the adult. I am currently trying to understand how skeletal muscle differentiation happens during embryonic development as well as during adult muscle regeneration after injury or disease using animal models and in vitro techniques.
Principal Investigator: Dr. Sam J Mathew
Plants mount highly elaborate, layered, and complex defenses against constantly invading pathogens. These multilayered defenses broadly termed as PAMP-triggered immunity (PTI) and effector triggered immunity (ETI), account for responses on perception of conserved molecular patterns present on a pathogen surface or to a specific pathogen effector secreted and sensed within the plant cell by a cognate resistance (R) protein, respectively. Although genetic screens and subsequent molecular approaches have identified several key immune players, our present understanding clearly suggests that signaling in ETI defy the conventional step-wise linear arrangements of signal receivers and transducers. Previously, we have proposed that effector activities that cause alterations in dynamics of protein interactomes between the R protein with positive and negative regulators directly mediate the sensing and transduction of signals. The broad goal of our research group is to unravel this mystery at a molecular level.
We utilize the Pseudomonas syringae-Arabidopsis thaliana model system, advantageous due to completely sequenced genomes of both organisms, to identify routes for immune signaling. Macromolecular associations of most defense players are assembled on lipid interfaces via unknown mechanisms. We have obtained preliminary evidences that indicate a role of inositol compounds in this assembly and in plant defenses in general. Inositol derivatives, initially identified as a source of phosphate storage in seeds, direct several key cellular processes such as mRNA export, apoptosis, plant hormone signaling and control of transcription. Inositol-modified lipids (phosphatidylinositols, PtdIns) determine architecture of most eukaryotic membranes. Inositol phosphates (InsPs) function as key secondary messengers. The significance of inositols is clearly elaborated in several human diseases such as Huntington disease and sickle cell disease. Our research aims to transcend the plant/anim al species barrier and further highlight the fundamental similarities in defense responses of higher eukaryotes.
In order to elucidate inositol signaling in immune responses we have divided our approach in several broad directions:
Principal Investigator: Dr. Saikat Bhattacharjee
The hallmark of any living organism is the ability to respond to external stimuli and internal cues. These responses involve modulations in the gene expression profile of the organism. In order to ensure optimal use of resources, gene expression in bacteria is tightly regulated at the level of transcription initiation. In most cases the regulation of transcription initiation occurs through the use of factors that can positively (activators) or negatively (repressors) affect transcription. These factors may be global or specific depending on the number of genes and range of cellular functions that they modulate. They bind to specific DNA sequences within the promoter region and can either inhibit or stimulate the RNA polymerase (RNAP) activity. In addition, many of these molecules bind to small metabolites and this binding event affects their interaction with DNA to ultimately modulate transcription of the corresponding genes. Overall, transcription factors interact with target sequences on DNA, with other trans factors and with different subunits of RNAP to achieve function.
The primary focus of my laboratory is to investigate the relevant molecular interactions (protein-DNA, protein-small metabolites, protein-protein) that are critical for regulating the activity of RNAP. At present, the molecules under scrutiny are :
1. FleQ - a global transcription regulator of flagellar and biofilms genes in Pseudomonas aeruginosa.
2. AraR - a transcription repressor from Bacillus subtilis that serves to differentially repress enzymes involved in arabinose metabolism as well as its own expression.
We use an integrated approach involving structural tools, biophysical techniques and biochemical methods to shed light on these interactions.
Principal Investigator: Dr. Deepti Jain
Food legumes represent major crops cultivated and consumed in India and other developing countries due to their high nutritional value and important role in maintaining the ecosystem. Powdery mildew is one of the most devastating fungal diseases limiting legume productivity in India. These obligate biotrophs alter plant cellular architecture and metabolism to acquire nutrients via specialized feeding structures (haustoria) while limiting plant defense responses. Chemical treatments used to control the disease are neither economical nor sustainable. Furthermore, despite the availability of a few powdery mildew resistant legume varieties, identity of the genes conferring resistance and knowledge of the underlying molecular events is limited.
Our main goal is to identify novel plant host genes that limit powdery mildew growth with no associated yield penalty and introduce them into agronomically important food legumes to increase durable resistance. We will integrate infection site-specific analyses, functional genomics and molecular genetics in the Medicago truncatula-Erysiphe pisi model system to identify novel host factors that limit powdery mildew growth at different developmental stages and translate functionally verified targets into food legumes. We envisage that factors able to limit pathogen growth at different developmental stages would be more difficult to overcome than resistance based on a single mechanism or mechanisms governed by a single gene.
Another major area of focus is to elucidate how obligate biotrophs modulate host metabolism to divert nutrients, especially sugars from the host plant for their sustained growth. We will utilize the Medicago -Erysiphe pathosystem to identify pathogen-induced molecular components of carbohydrate sink strength at the powdery mildew infection site. We will combine infection site-specific profiling, promoter, co-expression and gene ontology enrichment analyses to identify regulators of this process and construct putative regulatory networks with testable hypotheses. Using these approaches, we expect to identify key players modulating carbon (re)allocation at the infection site.
Principal Investigator: Dr. Divya Chandran