UTPAL S. TATU
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My research aims to decipher the functions of molecular chaperones in cellular context. Chaperones are well known for their ability to assist protein folding, facilitate protein assembly, prevent protein denaturation and renature misfolded proteins. Biochemical activities and molecular mechanisms of chaperone function have been elegantly studied by reconstituting purified components outside the cell. However the broader impact of chaperone function in cell growth and development is only beginning to be appreciated.
Molecular chaperone, HSP90, evolutionarily conserved regulates more than 200 proteins with respect to constitutive cell signaling and responses to stress. This chaperon has been used by cancer cells to regulate numerous oncoproteins and hence HSP90 inhibition seems to offer a unique anticancer strategy. In my lab, we carry out exploration of novel HSP90 inhibitors to combat cancer. The approach involves in vitro drug binding assay and animal experiments.
B. Veterinary healthcare:
Agrarian economies like India heavily depend on animals for their agricultural practices. Animal health care has been of major concern in most developed countries. With increase in the incidence of zoonotic diseases there is a growing demand to address animal infections in terms of their prevention and treatment. Further more there is a big gap between veterinary health care and technology applications in developing countries. My group is trying to bridge this gap by studying neglected animal infections such as animal trypanosomiasis using modern tools of biology. Our long term goal is to find better control measures as well as therapeutic strategies. Efforts are being made to develop better diagnostic tools as well as new drug development.C. Neglected infectious diseases:
It is well known that the parasite experiences a temperature shock of over 10°C during its entry in the vertebrate host. Furthermore, during febrile episodes in the patient the parasite is exposed to a heat shock (up to 41°C) due to rise in the body temperature of the host. How does the parasite react to these rapid temperature fluctuations? What are the protective mechanisms employed by the parasite to counter cellular damage? Experiments performed in my group in the last 10 year have shed some light on these mechanisms.
Surra is caused by Trypanosoma evansi infection. It is a veterinary protozoan disease most common in the cows, buffaloes, horses and other cattle. The disease has been listed as one of the major concern by World Organisation for Animal Health (OIE) in 2011 and is common in tropical countries. My laboratory works on understanding the role of chaperones in the progress of disease in host. We have shown important role of Heat Shock Protein 90 from T. evansi (TeHsp90) by using Hsp90 directed inhibitor called 17-AAG (17-allyl amino 17-demethoxy geldanamycin). We are now progressing towards starting animal trials against the disease using the above mentioned inhibitors.(Pallavi R et al., JBC 2010, Roy N et al., Plos One 2010)
Heat shock protein 90 plays diversified roles in different microbes. Like any other pathogen Giardia lamblia also uses heat shock protein machinery to survive under stress full conditions put forth by host. Mass spectrometric analysis of Hsp90 from G.lamblia, revealed a novel trans-splicing based expression of GlHsp90 in this minimalist protozoan parasite. We have recently shown that Hsp90 in Giardia is arranged as a split gene, HspN and HspC separated by 777 kb intergenic sequence. The full length Hsp90 transcript is a resultant of a novel trans-splicing phenomenon which is mediated by spliceosomal complex. The mature full length transcript has all the hallmarks of the canonical Hsp90. The protein band that corresponded to a region of around 80 kDa was identified to be GlHsp90. Hence we provide evidence for such a reconstruction mechanism at proteomic level. Sequencing of the junctional peptide by MS/MS provides evidence of functional full length Hsp90 in Giardia, a novel approach to identify trans-splicing event using mass spectrometry. (Nageshan RK et al., JBC 2011, Roy N et al., Biochim Biophys Acta 2011)
We are also examining the importance of Hsp90 in Entamoeba histolytica. The microbe is responsible for a most common clinical problem called as amoebiasis.D. Targeted Drug Discovery:
While deciphering the novel molecular targets and pathways my group also uses anasamycin antibiotics as model organic molecules to understand the role of heat shock proteins in stress during the infection.(Pallavi R et al., JBC 2010)
E. Model Systems:
In addition to examining infectious protozoa, my laboratory also uses Dictyostelium discoideum and Saccharomyces cerevisiae to understand functions of Heat shock protein 90 and its co-chaperones in Biology.(Sawarkar R, Roy N et al., J Mol. Biol. 2008, Wider D et al.,Mol Biochem Parasitol. 2009)1. Dictyostelium discoideum
2. Saccharomyces cerevisiae
F. Role of ER chaperones in protein folding:
My group is also examining folding of secretory proteins in the ER of animal cells. By reconstituting the oxidative folding of retinol binding protein (RBP) in isolated ER we are examining the mechanisms underlying selective retention of apo forms of RBP in the ER.(Sundar Rajan Selvaraj et al., Mol Biol Cell. 2008)
G. Proteomic and Bioinformatic activities:
In addition to the quest of understanding the chaperone biology in infectious and neglected diseases we constantly focus on the translational/application sciences by using 2DGE, mass spectrometry and bioinformatics analysis which ultimately culminates into leading proteomics research out comes in the country. My group plays a leading role in mining the proteome data from the variety of biological exudates, coming directly from infected human/animal subjects by using state of the art proteomics and bioinformatics tools . We have successfully worked on clinical proteome of Plasmodium falciparum, Plasmodium vivax infections.(Kumar Y et al., Proteomics 2004, Khachane A et al., J Proteome Res. 2005, Pallavi R et al., Plos One 2011, Acharya P et al., Proteomics CA 2009)