A. Screening for GPCR selective Novel Chemical Entities (NCEs):
We employ following 3 types of live cells functional assays, which measures G-protein coupled receptor (GPCR) dependent formation of secondary messengers or β-arrestin recruitment to GPCRs (as shown in the cartoon below) to discover selective agonist and antagonists of target GPCRs. We are focused to discover novel and high affinity ligands for 9 GPCRs (KOR, GPR40, HTR2C, HTR6, HRH3, CXCR3, CXCR4, CMKLR1, DRD5), which can be developed for the treatment of various CVS and CNS disorders.
GloSensor assay for the measurement of Gi- or Gs-coupled receptor activity
NFAT-RE assay for the measurement of Gq-coupled receptor activity
Tango assay to determine the agonist dependent β-arrestin recruitment to the orphan GPCRs
B. Primary cultures of neurons and glia:
We culture primary brain cells (neurons, astrocytes and microglia) from neonatal mice (P0-1) to elucidate the molecular mechanisms of GPCR signaling in various CNS pathologies. Our long term goals are to find the mechanisms and targets that modulate neurotrophin and gliotrophin expression in depression, dementia and chronic pain like conditions.
C. Understanding the etiology of treatment resistant depression
Our overarching goal is to understand the molecular mechanisms of treatment resistant depression and molecular determinant of
antidepressant response. To achieve this, we are investigating the expression patterns of molecular correlates and architectural
plasticity (e.g., spine density, neuronal arborization) and levels of neurotrophins in various brain regions) in rodent models of
depression. Also, using cutting-edge chemogenetic tool - Designer Receptor Exclusively Activated by Designer Drug: (DREADD),
we are investigating the involvement of monoaminergic and glutamatergic neurons in depression with a long term goal to discover
novel targets/approaches for the treatment of depressive disorders.
D. Dementia:
A range of cognitive deficits that spans across several neuropsychiatric disorders is a huge unmet medical need worldwide.
Currently available drugs’ (acetylcholine esterase inhibitor’s or NMDA modulator) effects are very modest and vary in patient
population. Furthermore, our understanding of the molecular anomalies that affect neuronal and circuit functions to give
rise to the cognitive deficits associated with psychiatric disorders is very much superficial. With long term goals of
finding new druggable target for the cognitive enhancement, we are focused on delineating the function and interaction
of key brain networks using DREADD technology, and investigating the signaling mechanisms of GPCRs (e.g., DRD5 and 5-HT6)
that are expressed selectively in a network or a population of neuron in the brain. We are using following behavioral
measurements to achieve these broad objectives.
I. Object Recognition Test for declarative memory
II. Morris water maze test for spatial and temporal memory
III. Eight-arm radial maze test for working memory
IV. Active and passive avoidance for aversive cue associated learning and memory
E. Neuropathic Pain
Neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory nervous system”. Neuropathic pain is also comorbid with several diseases or injuries of the peripheral or central nervous system, and has a substantial impact on the quality of life and mood. Existing therapeutics for the neuropathic pain are modestly effective and have severe adverse effects. Poor understanding about the etiology of neuropathic pain is a major obstacle for the development of better therapeutics. Therefore, we are investigating the molecular mechanisms of G-protein coupled receptors and neurotrophic factors involved in the neuropathic pain to find out new druggable target of chronic pain disorders. Currently, we are using chronic constriction injury of sciatic nerve (as shown in figure below) in C57BL/6J mice to develop neuropathic pain condition.