The main area of research in my laboratory is RNA biology, which has become very important in the last decade following the discovery that majority of the human (and other mammalian) genome gives rise to non-protein coding transcripts. We have taken a study through the phases of bioinformatics prediction, in vitro validation, in vivo testing and clinical studies. My group proposed that the loss of miR-29 family of miRNAs is a common feature of a number of neurodegenerative diseases (Drug Discovery Today, 2009). Several international groups are now exploring the relevance of this miRNA as a target in neurodegenerative diseases. Our work showed that a set of non-coding RNAs are dysregulated in cultured neuronal cells expressing pathogenic, polyglutamine-TATA Binding Protein (PLoSONE 2007; RNA Biology 2012). Notably, we revealed that miR-29a/b, a critical regulator of apoptosis, was down-regulated not just in Spinocerebellar Ataxia 17 (SCA17) but a number of other neurodegenerative conditions. Using miRNA-proteomics we showed that VDAC1, an outer mitochondrial membrane pore, with very weak binding sites for the miRNA, was strongly up-regulated in neurons when the miRNA was down-regulated (PLoSONE 2012). My work veers away from the general notion in the field since we showed that from a panel of predicted miRNA targets, including Bcl2, PUMA, BACE1 and VDAC1, the weakest bioinformatics predictions were the most amenable to in vivo modulation (RNA, 2014). We have recently shown the involvement of interferon in the aberrant miRNA expression in SCA17 (J. of Neuroinflammation, 2017).
We have developed a novel approach to knock-down miRNAs specifically in the brain using a combination of cell-penetrating peptide, neurotropic peptide and anti-miRNA (RNA, 2014). Using this combination, we could show that brain specific, acute loss of miR-29a/b could lead to rapid neuronal cell death and ataxia like symptoms. The mice developed hallmarks of ataxia like abnormal gait, hind limb clasping defect and reduced step length. This in vivo knockdown has been critical in showing that the transient loss of a single miRNA can result in apoptosis and ataxia like symptoms in mice (RNA, 2014). These methods, being novel, were independently published (JoVE. 2015) and the results have now been validated by other international groups establishing miR-29a/b as as a target in neurodegenerative diseases, as originally proposed by our group.
As a member of a group that first reported the anti-HIV potential of certain miRNAs, leading to highly cited early publications and patents, I have been leading a long-term clinical study in collaboration with Lt. Dr. Sunidhi Solomon, YRGCare, where a panel of anti-HIV miRNAs were monitored in a novel cohort of about 70 HIV patients (Rakesh Dey et al. 2016) . On the basis of this study, reduced expression of miR-382-5p and miR-155-5p has been proposed as critical factors in slowing the progression of HIV infection into disease. This has led to our inclusion in a DBT sponsored 5-year study involving an international team drawn from three countries, under the aegis of the International AIDS Vaccine Initiative.
We also proposed that cytoplasmically inherited RNA provides an epigenetic mechanism by which gene expression from the zygotes' genome maybe modulated (Soni et al. 2013). The transgenerational inheritance of miRNA, miR-34, and the loss of maternal miR-34 resulting in defects in brain development, especially mid-brain - hindbrain boundary formation, were shown by my group (Soni et al. 2013). Recently, we found a novel long non-coding RNA from Zebrafish, now christened Durga, that regulates the expression of Kalirin, a protein involved in synaptic remodelling. The expression of Durga during early development is critical for the timely induction of Kalirin and ectopic expression of Durga results in neurons with a severe reduction in spine density (Sarangdhar et al. 2017). We have also created a widely used and well cited resource for miRNA expression profiles from nearly pure cultures of neurons and glia in the mammalian brain, in collaboration with Ruth Luthi-Carter, a long standing collaborator. This resulted in the knowledge that during development, the role of miRNAs is to restrict inappropriate expression of target genes. Thus, glial miRNAs shut down the expression of neuronal genes and vice versa(Jovičić et al. 2013).
These projects have given me an opportunity to work with diverse model organisms: yeast, zebrafish, mammalian cells, mouse and clinical patient samples