Biochemistry, UDSC

Research

Research Highlights of Department for Last 5 years



Theme of Research Activities in the Department

"Development of Molecular Strategies to Combat Various Human Diseases"


(Diagnostics, Drugs, Drug Delivery, Vaccines, Mechanistic Insight to combat Tuberculosis, Cancer, Cardiovascular diseases, Malaria, Viral diseases)


Professor Anil K. Tyagi

(Specialization:
Tuberculosis with special reference to the development of new TB vaccines and drug discovery against TB)

Dr. Tyagi’s laboratory has been working on the development of vaccines against tuberculosis.  Detailed evaluation of the promising candidate vaccines against aerosol infection of M. tuberculosis in guinea pigs was carried out by using heterologous prime boost approach.  In this study, three regimens comprising of (i) recombinant BCG overexpressing 85C, (ii) recombinant BCG overexpressing β-crystallin as the priming agent followed by boosting with a DNA vaccine expressing the same antigen and (iii) BCG as priming agent followed by boosting with DNA vaccine expressing β–crystallin showed extremely good results and imparted a superior and sustained protection in comparison to the present BCG vaccine both on the basis of reduction in the bacillary load in lung and spleen as well as histopathological changes.  The Tuberculosis Vaccine Clinical Trial Expert Group (TVCTEG) of the Department of Biotechnology, Government of India, has in principle recommended these vaccine regimens for human clinical trials.  Currently, upstream pre-clinical work on these candidate vaccines is in progress so that eventually the human clinical trials can be initiated.

Few years ago, focusing towards the development of new anti-tubercular therapeutic molecules, Dr. Tyagi’s laboratory started structure determination of important mycobacterial proteins and characterization of these novel drug targets.  His laboratory has already determined the structure of four new mycobacterial proteins and the process of developing inhibitors against these targets is in process.  In view of the importance of mymA operon in the survival of Mycobacterium tuberculosis, Dr. Tyagi’s laboratory has characterized in details one of the important enzymes of this pathway and determined its structure.   By using the targets identified in his laboratory, Dr. Tyagi and colleagues have identified several lead molecules for the inhibition of mycobacteria.

In a multicentric project, with Dr. Tyagi’s laboratory being the nodal constituent, it has been shown that Mycobacterium indicus pranii (earlier name Mycobacterium w.) has been the predecessor of highly pathogenic Mycobacterium avium intracellulare complex (MA/C) that did not resort to parasitic adaptation by reductional gene evolution and therefore, preferred a free living life-style.  Further analysis suggested a shared aquatic phase of MA/C bacilli with the early pathogenic forms of Mycobacterium, well before the latter diverged as `specialists’.  This evolutionary paradigm affirms to marshal our understanding about the acquisition and optimization of virulence in mycobacteria and determinants of boundaries therein.  Following these studies, the sequencing of complete genome of Mycobacterium indicus pranii has been carried out at University of Delhi South Campus and published recently.  This paper represents publication of the first completed genome of a new bacterial species from our country.

Professor Vijay K. Chaudhary

(Specialization: 
Development of novel reagents for diagnostic test for infectious diseases using state-of-the-art protein engineering technologies including human antibodies)

Dr. Chaudhary’s group has developed a rapid test “TBConfirm“ for the culture confirmation of M. tuberculosis. The technology of production TBConfirm test has been transferred to M/s SPAN Diagnostics Limited, Surat.  The MoA/MoU was signed on 26th August 2011 by Professor Umesh Rai, Director, UDSC; Dr Pradeep Desai, Chairman, SPAN Diagnostics Ltd. and Dr Bindu Dey, Advisor, DBT in the presence of Professor Dinesh Singh, Vice Chancellor, University of Delhi and Dr. M.K. Bhan, Secretary, DBT.   The kit has performed well in multi centric trial with near 100% sensitivity and 100% specificity.  The product “TBConfirm” will be available soon in the market as the company is about to get commercial manufacturing license.  Under a CSIR-NIMITLI project Technology is being developed to construct a phage displayed human antibody library containing 109 independent clones.

Professor P.C. Ghosh

(Specialization: 
Drug Delivery using Liposomes and Nanoparticles as Carriers)

Prof. P.C. Ghosh’s laboratory mainly focuses on drug delivery using liposomes, PLGA nanoparticles and solid lipid nanoparticles as carriers of therapeutic molecules for the treatment of infectious and cancerous diseases. Prof. Ghosh’s group has successfully delivered various toxins and therapeutic molecules to cancerous cells using targeted and long circulatory liposomal formulations.  The group has also developed cholesterol hemisuccinate vesicles that were shown to efficiently deliver Amphotericin-B for the treatment of fungal infection, aspergillosis. Moreover, his group has developed PLGA nanoparticles loaded with herbal compounds like curcumin and piperine for the chemotherapeutic interventions against cancer. Another PLGA nanopreparation entrapping monensin was shown to be highly effective in inhibiting the growth of malaria parasite P. falciparum in culture. Recent activities in the lab involves use of various liposomal formulations of carboxylic ionophores for anti-malarial therapy. Prof. Ghosh’s group has also used stearylamine liposomes for delivery of anti-miR-191 into breast cancer cells.

Professor Debi P. Sarkar

(Specialization:
Host-virus Interactions/Molecular Cell Biology/Virology)

Dr. Sarkar’s group attempted to perform a global investigation of protein alterations in hepatoma cells in response to Sendai virus infection. This study is the first step towards improving our understanding of the complex cellular events that occur during virus infection in liver cell line. The differential profiling of liver cells with and without virus infection was performed first by conventional two-dimensional gel electrophoresis and also by the improved 2D-DIGE (Difference gel electrophoresis). This will help us to elucidate the virus –host interactions which may help in increasing the efficiency of virosome mediated delivery for liver directed gene therapy and for developing new vaccines based on viral vectors. Relevant high end techniques of 2D-DIGE have been thoroughly standardized and work is under way. No publishable results are ready yet.

Preclinical gene therapy studies with a gunn rat model, supported jointly by NRDC, New Delhi and AECOM, USA is going on for treating jaundice (Crigler-Najjar Syndrome, Type I Jaundice) with Sendai virus based F-virosome entrapped bilirubin-UDP glucouronysyl transferase (BUGT) gene to liver cells. Negotiation with various pharma companies through NRDC, New Delhi is going on with our PCT patent published on March, 2011 for a clinical trial. Details can’t be disclosed at this moment for the interest of confidentiality agreement.

Professor Suman Kundu

(Specialization:
Structure-Function Relationship and Protein Engineering in Hemoglobins and Artificial Blood Substitutes; Diagnosis of Hemoglobinopathies; Rational Drug Design (Cardiovascular Diseases, Cancer)

Dr. Kundu’s group has extensively investigated several new hemoglobins from various organisms that led to novel insight into their stability, regulation of ligand binding and putative function. His lab has provided insight into aggregation and fibril formation of some important hemoglobins. His group has designed proof-of-principle mass spectrometric, FTIR and Mossbauer spectroscopic methods for precise identification of mutations leading to structural hemoglobin disorders and other blood disorders. Utilizing all the knowledge gained over the years, his group is currently investigating ways to improve stabilities in recombinant hemoglobin using protein engineering technologies to be able to design artificial blood substitutes. Dr. Kundu’s group provided the first three-dimensional model for Dopamine-b-Hydroxylase, a drug target for complex traits. The structure conforms very well to known biochemical data. Several SNPs have been mapped onto the structure and testable hypotheses have been forwarded as to their influence on structure-function relationship of the protein. The model provides an impetus for drug design, especially against cardiovascular diseases. His lab has screened several small molecule libraries against the therapeutic enzyme with success. Few of the molecules showed promising inhibition in vitro and regulated high blood pressure in rat models of hypertension.

Professor Alo Nag

(Specialization:
Molecular mechanisms of oncogenesis; Cell cycle regulation; Tumour suppression pathways; Role of posttranslational machinery; Discovery of novel therapeutic targets against cancer; Drug delivery)

The major research interest of Prof. Alo Nag’s laboratory is to enhance basic understanding of the molecular mechanisms of tumor development. Ongoing research projects are mostly designed to investigate the key molecular events responsible for transformation of normal cells into cancerous cells. The long term research goal is to unravel the root cause of the disease and exploit this knowledge to develop improved strategies to combat cancer.

With regard to the above objective, the lab is actively involved in investigating unknown oncogenic functions of Human Papillomavirus. This as an effort towards identification of novel molecular targets against HPV related malignancies including Cervical cancer, a major killer among Indian women.  Prof. Nag’s group has uncovered several novel mechanisms of HPV mediated oncogenesis.

The lab is also interested in another cancer therapy target, FoxM1, a master regulator of cell cycle implicated in oncogenesis and metastasis. This lab is particularly interested in studying the mechanism that underlie Fox M1 upregulation during tumorigenesis. Recent findings from the lab have revealed interesting roles of posttranslational mechanisms in modulation of FoxM1 function as well as its expression in cancer cells.  

Study of tumor suppression mechanisms  is yet another research focus of this lab. Prof. Nag’s group is trying to address the enigmatic functions of Cytoglobin (CYGB). Their findings not only confirmed CYGB’s anti-proliferative role but also provided novel evidences for its involvement in cell cycle regulations.


Dr. Amita Gupta

(Specialization:
Molecular mechanisms of action of toxin-antitoxin loci, identification of new biomarkers for detection of TB, development of molecular assays and immunoassays for infectious diseases)

Our group has been working on identification and characterization of Toxin-antitoxin (TA) loci of M. tuberculosis (Mtb).  In this context, we have characterized genome-wide TA loci of Mtb for their activity and killing action.  We have further delineated the expression profile of all the hitherto identified TA loci of Mtb and identified those loci that play a crucial role in Mtb survival under nutritional stress and chemical/antibiotic stress.  We are further characterizing the regulatory elements of some of these loci in order to understand the signals that lead to their activation and deactivation.  We have also initiated work on identifying drug-resistance markers for Mtb that can be used to develop molecular assays to detect drug resistance.

Dr. Garima Khare

(Specialization:
Drug discovery against Tuberculosis and understanding the host-pathogen interactions involved in Tuberculosis)

The research interests of the laboratory primarily pertain to the identification of novel inhibitors against Mycobacterium tuberculosis, the causative agent of tuberculosis, which can be developed into potent drugs against TB. The work involves the use of structure based strategy as well as high throughput phenotypic screening based strategy to identify small molecules against important drug targets as well as against the growth of Mycobacterium tuberculosis in vitro and inside macrophages. Subsequently, the cytotoxicity assays are performed and the promising inhibitors are then evaluated in mice model of tuberculosis to check the efficacy of the compounds towards the treatment of the disease. In addition, the research efforts are dedicated towards the understanding of host-pathogen interactions involved in TB pathogenesis and role of important mycobacterial genes in the pathogenesis and growth of the pathogen in the host by developing gene knockout mutants and correlating the loss of gene function with the establishment and progression of the disease and ability of the mutant pathogen to survive in the host.

Future plans include reengineering/optimization of candidate inhibitory compounds identified in the lab to increase their potency and efficacy towards the inhibition of M.tuberculosis growth. Attempts to develop more rapid and accurate inhibitor screening strategies against M.tuberculosis would be made. The efforts would also be directed towards the understanding of the stress responses in the bacteria when it encounters the host milieu and trying to identify pathways associated with acidic stress in the bacteria which would be crucial for adaptation and survival of the pathogen under harsher conditions.

Dr. Suneel Kateriya

(Specialization:
Molecular basis of the rhodopsin mediated signaling, Optogenetics, Channelopathy and Ciliopathy)

Our lab is working towards understanding photoreceptor mediated signaling in Algae, pathogenic protozoa and human bacterial pathogens. We are also developing light-sensitive protein tools and nano-device(s) for Cell Biology, Neurosciences and clinical applications by using inter-disciplinary approaches.

 


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