Annual Report 2015 Rajiv Gandhi Centre for Biotechnology
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ANNUAL REPORT 2 0 1 5 Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram, Kerala Phone: +91 471 2341716, 2347975 Fax: +91 471 2348096, 2346333 E-mail: [email protected] Website: www.rgcb.res.in Contents DIRECTOR’S REPORT 05 CANCER BIOLOGY Cancer Research Program - 1 09 Cancer Research Program - 2 17 Cancer Research Program - 3 26 Cancer Research Program - 4 35 Cancer Research Program - 5 50 Cancer Research Program - 6 61 Cancer Research Program - 7 67 Cancer Research Program - 8 71 Cancer Research Program - 9 79 CARDIOVASCULAR DISEASE & DIABETES BIOLOGY Laboratory - 1 107 Laboratory - 2 121 Laboratory - 3 132 Labouratory - 4 139 CHEMICAL & ENVIRONMENTAL BIOLOGY Chemical Biology Laboratory - 1 142 Chemical Biology Laboratory - 2 149 Molecular Ecology Laboratory 154 Environmental Biology Laboratory 162 NEUROBIOLOGY Molecular Neurobiology Laboratory 171 Neuro Stem Cell Biology Laboratory 177 Human Molecular Genetics 184 Neuro Bio-physics Laboratory 191 PLANT DISEASE BIOLOGY & BIOTECHNOLOGY PDBB Laboratory - 1 196 PDBB Laboratory - 2 206 PDBB Laboratory - 3 212 PDBB Laboratory - 4 217 REPRODUCTIVE BIOLOGY Molecular Reproduction Laboratory - 1 224 Molecular Reproduction Laboratory - 2 236 TROPICAL DISEASE BIOLOGY Mycobacteria Research Laboratory 247 Cholera Research Laboratory 256 Leptospira Biology Laboratory 264 Molecular Virology Laboratory 266 Viral Disease Biology Laboratory - 1 271 Viral Disease Biology Laboratory - 2 280 Malaria Biology Laboratory 284 Microbiome Research Laboratory 293 RGCB CORE SERVICE FACILITIES 297 RGCB RESEARCH ENGINEERING SERVICES 312 RGCB ADMINISTRATION AND STAFF LIST 316 RGCB PROGRAMS 324 RGCB SKY GREEN 326 DIRECTOR’S REPORT Two roads diverged in a wood and I took the one less traveled by, and that has made all the difference. - Robert Frost And that was what RGCB did. Without losing focus on our primary mandate as an R&D institute, we also took care not to remain in an ivory tower. We delivered our unique expertise in modern biology for public service. Our Molecular Forensics group came to the state’s service at a time of great calamity. The unfortunate fireworks tragedy at Puttingal temple killed over 100 people. Many bodies were charred beyond recognition. RGCB Molecular Forensics experts worked day in and day out to DNA type these unfortunate victims and allow grieving families claim bodies to perform last rites of their beloved. True to its character RGCB waived all service charges for the DNA fingerprinting in this time of national tragedy. Our success in research continues. Our Neuro-Stem Cell Biology group, using reporter systems and in utero electroporation, qualitatively unraveled the existence of NIHes-1 expressing neural stem cells from the cohort of dependent progenitors throughout the mouse neocortical development. Notch signaling pathway and its downstream effector Hes-1 are well known for their role in cortical neurogenesis. Though Hes-1 expression is maintained in neural progenitor territory at all times, a simple shift from Notch-independent to -dependent state makes it pleiotropic as the former maintains the neural stem cells in a non- dividing/slow-dividing state, whereas the latter is very much required for maintenance and proliferation of radial glial cells. Jackson James et al, thus provide an additional complexity in neural progenitor heterogeneity regarding differential Hes-1 expression in the germinal zone during neo-cortical development. RGCB’s Cancer Research Program provided data on the vital role of DEPTOR in survival of cervical squamous cell carcinoma (SCC). DEPTOR, an endogenous inhibitor of mTOR complexes is de-regulated in cancers and was found to be overexpressed in both cervical SCC cell lines and tissues. It’s silencing in cervical SCC cells induced apoptosis, mainly by up-regulation of p38 MAPK and by inhibiting PI3K/AKT pathway via a feedback inhibition from mTORC1-S6K. DEPTOR silencing resulted in reduced expression of the nitric oxide synthases iNOS and eNOS, as well as increased activation of ERK1/2 and p38 MAP kinases. In summary, DEPTOR is found to promote survival of cervical SCC cells and its reduction induced apoptosis via differential effects on PI3K/AKT and p38 MAPK. Priya Srinivas et al analyzed the effect of Plumbagin (PB) and structurally related naphthaquinones on BRCA1/2 silenced prostate cancer cells and the ability of PB to target cancer stem cells. PB has putative role in tumor suppression in BRCA defective cancers and has the ability to directly target cancer stem cells (CSCs) and holds promise for novel therapeutic approaches against BRCA mutated cancers as well as CSCs. Ruby John Anto and colleagues studied the anticancer activity of 3,5-dihydroxy Q1 -4-ethyl-trans-stilbene (DETS)- a natural stilbene, with a structural similarity to resveratrol (trans- 3,4,5-trihydroxystilbene), first identified as bioactive bacterial secondary metabolite isolated from Bacillus cereus associated with a rhabditidentomopathogenic nematode and reports that the compound showed maximum cytotoxicity toward the human melanoma cell line, [A375, IC50: 24.01 μM] followed by cervical [HeLa-46.17 μM], colon [SW480- 47.28 μM], liver [HepG2- 69.56 μM] and breast [MCF-7- 84.31 μM] cancer cells. DETS, like resveratrol, down-regulates the expression status of major molecules contributing to melanoma progression, such as BRAF, β-catenin and Brn-2, all of which converge in MITF-M, the master regulator of melanoma signaling. RGCB once again demonstrated its value in leading Translational Cancer Research. Oral leukoplakia is a potentially malignant lesion of the oral cavity, for which no effective treatment is available. We investigated the effectiveness of curcumin, a potent inhibitor of NF-kB/COX-2, molecules perturbed in oral carcinogenesis, to treat leukoplakia. Subjects with oral leukoplakia were randomized (1:1 ratio) to receive orally, either 3.6 g/day of curcumin or placebo, for 6 months. The primary endpoint was clinical response obtained by bi-dimensional measurement of leukoplakia size at recruitment and 6 months. Histologic response, combined clinical and histologic response, durability and effect of long-term therapy for an additional six months in partial responders, safety and compliance were the secondary endpoints. Combined clinical and histologic response assessment indicated a significantly better response with curcumin. The treatment did not raise any safety concerns. Treatment of oral leukoplakia with curcumin (3.6 g for six months), thus was well tolerated and demonstrated significant and durable clinical response for 6 months. Findings from the Phase – IV trial comparing the 2 versus 3 doses of quadrivalent HPV vaccine among young Indian girls, support the WHO recommendation of two doses, at least six months apart, for routine vaccination of young girls. While our non-randomized comparisons confirm that the immune response following two doses given at 6 months apart is non-inferior to that of three doses, one dose vaccination was associated with lower antibody levels. Nevertheless, the single dose antibodies were as avid as the two and three dose antibodies as reflected by the similar geometric mean avidity indices and also induced detectable titers of neutralizing antibodies although at a lower level. Our initial results provide the first evidence that the lower vaccine-induced antibody levels following one dose of quadrivalent HPV vaccine provide similar protection against vaccine-targeted HPV infections as the higher antibody levels from two or three doses over a four-year follow-up period. Our preliminary results following one dose of quadrivalent vaccine are promising and suggest that future trials of HPV vaccines should include a single dose arm. A single- dose HPV vaccination offers the best chance to overcome the barriers currently prohibiting vaccine uptake globally; on condition it provides strong and sustained protection against HPV infection in the long term. Our plant biotechnologists have focused on improving our indigenous crop varieties. Over the last century, the commercial production of black pepper (Piper nigrum) has been significantly affected by ‘quick wilt’ disease caused by the oomycete pathogen, Phytophthoracapsici. There are no varieties of black pepper that can completely resist this disease and progress in understanding the molecular components of this phyto-patho- system has been severely hampered due to lack of proteome or transcriptome databases in the plant. Manjula S. et al explored the potential of a transcriptome-assisted label-free quantitative proteomics approach for elucidation of leaf proteome of black pepper when challenged with P. capsici. This simple and integrative approach has brought out novel and comprehensive insights into the complex network of proteome changes involved in black pepper- Phytophthora interaction, which is of practical interest for developing crop improvement strategy in this major spice crop. The study also provides convincing evidence on the effectiveness of a transcriptome-based label-free proteomics approach for elucidating the host response to biotic stress in non- model crop species like P. nigrum. 3’ UTR regulation plays crucial rule in most of the diseases, and the non-canonical PAP, Star-PAP has been identified to be a key player in this. Rakesh Laishram and colleagues demonstrate the role of phosphorylation in regulation of specific target gene/UTRs. Similarly, defining the phosphorylation sites on Star-PAP mediated by CKIα/PKC or other kinases could help in understanding