Ph.D. Student, CSIR-Central Drug Research Institute
Identification and validation of important drug target for learning and memory
We in our national laboratory at CSIR-CDRI do identification and validation of important receptor targets for learning and memory. My research involved characterization of the G- protein coupled receptor (GPR40) also known as Free fatty acid receptor-1 in diabesity (diabetes and obesity) induced co-morbid psychiatric disorders (cognitive decline). In this study, we for the first time reported that docosahexaenoic acid (DHA commonly known as fish oil) explicitly works through GPR40 in the brain and the beneficial effects of DHA in CNS occurs via GPR40. Through our finding, we also propose that GPR40 agonist (DHA) enhances cognitive performance in mice models of diabesity. Finally, using CNS specific drug delivery, we demonstrated that GPR40 antagonist blocks behavioral and biochemical beneficial effect of DHA.( Neurobiology of Disease , Accepted). Further, we have also found that hypothalamic GPR40 is essential for anti-depressant action of DHA via modulation of the HPA axis. My Research with NMDA antagonist (Dizocilpine), provided a unique mechanism to enhance memory in healthy mice by increasing expression of NMDA receptor. Moreover, this mechanism also increased essential biomarkers of synaptic plasticity. This study was presented at Alzheimer's Association International Conference, 2016 at Toronto and got published in Alzheimer's and Dementia (http://dx.doi.org/10.1016/j.jalz.2016.06.1449). Additionally, we also do compound screening on GPR40 and 5-HT2C receptor to identify novel chemical entities for anti-obesity and anti-diabetic drug treatment using NFAT-RE assay(Book chapter published 2016). Finally, my lab focuses to identify important drug targets of life style disorders associated psychiatric abnormalities, which could be further useful for pharmaceutical industry to develop drugs for future and cure incurable diseases like Alzheimer's.
Abstract: G protein-coupled receptors (GPCRs) are widely known to modulate almost all physiological functions and have been demonstrated over the time as therapeutic targets for wide gamut of diseases. The design and implementation of high-throughput GPCR-based assays that permit the efficient screening of large compound libraries to discover novel drug candidates are essential for a successful drug discovery endeavor. Usually, GPCR-based functional assays depend primarily on the measurement of G protein-mediated second messenger generation. However, with advent of advanced molecular biology tools and increased understanding of GPCR signal transduction, many G protein-independent pathways such as β-arrestin translocation are being utilized to detect the activity of GPCRs. These assays provide additional information on functional selectivity (also known as biased agonism) of compounds that could be harnessed to develop pathway-selective drug candidates to reduce the adverse effects associated with given GPCR target. In this chapter, we describe the basic principle, detailed methodologies and assay setup, result analysis and data interpretations of the β-arrestin2 Tango assay, and its comparison with cell-based G protein-dependent GPCR assays, which could be employed in a simple academic setup to facilitate GPCR-based drug discovery.
Pub.: 02 Mar '16, Pinned: 03 Jun '18
Abstract: G protein-coupled receptors (GPCRs) act as a relay center through which extracellular signals, in the form of neurotransmitters or therapeutics, are converted into an intracellular response, which ultimately shapes the overall response at the tissue and behavioral level. Remarkably in similar ways, epigenetic mechanisms also modulate the expression pattern of a large number of genes in response to the dynamic environment inside and outside of the body, and consequently overall response. Emerging evidences from the pharmacogenomics and preclinical studies clearly suggest that these two distinct mechanisms criss-cross each other in several neurological disorders. At one hand such cross-talks between two distinct mechanisms make more challenging to understand the disease etiology, while on the other hand if dealt appropriately, such situations might provide an opportunity to find novel druggable target and strategy for the treatment of complex diseases. In this review article, we have summarized and highlighted the main findings that tie epigenetic mechanisms to GPCR mediated signaling in the pathophysiology of central nervous system (CNS) disorders, including depression, addiction and pain.
Pub.: 29 Mar '16, Pinned: 03 Jun '18
Abstract: G protein-coupled receptors (GPCRs) are modulators of almost every physiological process, and therefore, are most favorite therapeutic target for wide spectrum of diseases. Ideally, high-throughput functional assays should be implemented that allow the screening of large compound libraries in cost-effective manner to identify agonist, antagonist, and allosteric modulators in the same assay. Taking advantage of the increased understanding of the GPCR structure and signaling, several commercially available functional assays based on fluorescence or chemiluminescence detection are being used in both academia and industry. In this chapter, we provide step-by-step method and guidelines to perform cAMP measurement using GloSensor assay. Finally, we have also discussed the analysis and interpretation of results obtained using this assay by providing several examples of Gs- and Gi-coupled GPCRs.
Pub.: 02 Oct '17, Pinned: 03 Jun '18