Project 1: Cancer Biology
To understand the role of differential expression of p53 isoforms in Human cancer
TP53 is a tumour suppressor gene, involved in maintaining genomic integrity by controlling cell-cycle progression and cell survival. It is the most frequently altered gene in human cancers. Several studies from our laboratory as well as others, report the importance of translational regulation of p53 in determining cellular fate. It has twelve isoforms; out of which Δ40p53 is the one which is translated from the same p53 mRNA using an IRES element (Ray et al. EMBO reports 2006). The translational regulation of p53 involves interaction of different proteins with 5’ UTR and 3’ UTR of its mRNA. Several proteins can bind specifically to the 3’UTR and can enhance the cap dependent as well as cap independent translation of p53 (Sharathchandra et al. RNA Biology 2012; Khan et al, Oncogene 2013). Moreover, these proteins are also known to have an interplay with certain non-coding RNAs, particularly miRNAs that bind to the 3’UTR of p53 mRNA (Katoch et al. Nucleic Acids Res. 2017). In human cancers, miRNAs as well as lncRNAs can regulate the p53 tumor suppressor pathway or vice-versa. We are interested to investigate how the isoforms, specifically Δ40p53 regulates mRNAs and non-coding RNAs to control the cell fate.
We would also like to extend our study at NIBMG (in collaboration with the laboratory of Dr. Srikanta Goswami), to understand the p53 translational control in cell proliferation, in the context of specific cancer. Given that human cancer (such as Pancreatic cancer and Colorectal carcinoma) is characterized by profound aneuploidy as well as significant intra-tumoral genomic heterogeneity, a clear understanding of how p53 participates in genome stability mechanisms would provide important insights into disease pathogenesis and ultimately treatment. In this respect we aim to investigate the ratio of different p53 isoforms in cancer tissue samples. We would like to look at the overall transcriptome levels in the cancer tissue samples, bearing wild type as well as mutant p53. This would further be correlated to aggressiveness of the disease and traced back to look for RNA levels of different p53 target genes in those samples. This would help us identify different cellular molecules such as mRNA, miRNA or lncRNA playing a role in progression and regulating the severity of cancer. Moreover, since p53 is known to control several methyltransferases, it would be interesting to study whether the p53 isoforms cause differential modification at promoters (such as methylation/demethylation) and if so, then how are the downstream target genes affected in different cancers. In addition to tissue samples, we would also like to look for cellular RNA signatures in serum levels as well, so that they could be used for early prognosis of disease thereby helping in cancer treatment.
Project 2: Infectious Disease Biology
Understanding the host genetic determinants of RNA virus pathogenesis
My laboratory at the Indian Institute of Science has been studying the biology and pathogenesis of several RNA viruses, such as hepatitis C and Coxsackie B3 virus. In continuation of my interests on RNA viral diseases, here at NIBMG I am involved in research on Dengue virus (DENV). Dengue disease in humans manifests itself in different forms varying from a non-symptomatic infection to the one that shows mild disease symptoms and some which manifests as a severe disease that includes symptoms related to haemorrhage (DHF) and shock syndrome. The severe form of the disease is becoming more common in our country and large gaps in knowledge exist in our understanding of the specific molecular reasons behind the phenomenon. In collaboration with my colleague Dr. Sreedhar Chinnaswamy, we are interested to know if human genetic variation at immune-related gene loci can be specific determinant of the severe form of the disease. The leads obtained from our studies on human patients will be tested in DENV-infected cell culture and mice models in order to understand molecular events/pathways that lead to severe forms of the disease, so that better intervention strategies can be deduced to manage the disease.
Selected Publications on HCV and CVB3