Research
Our lab believes in the philosophy of Bench-to-Bed side, where we strive to dig deep into the basic biological processes using various research models and apply the acquired knowledge to identify new drugs/drug targets. In line with this philosophy, our lab has multiple projects at the interface of Basic & Applied Biology, corroborated by our high impact publications and patents.
Model systems:
- Rodent models – primary neuron cultures, including dorsal root ganglions, cortical neurons, hippocampal neurons; sciatic nerve injury, spinal cord injury, optic nerve injury etc.
- Human iPSC-derived neurons for modeling various neurological diseases and understanding basic biological processes
- Cell lines – HEK293, HeLA, PC12, 3T3 etc.
Our Studies:
Our studies focus on how mRNAs are stored in axons and how they come out of the storage depots in response to injury. We uncovered a previously unidentified role for SGs in axon regeneration.
Specifically, we showed that SG core protein G3BP1 localizes to axons in the peripheral nervous system (PNS); axonal G3BP1aggregates into SG-like structures, and these structures disassemble during axon regeneration. G3BP1 inhibits axonal protein synthesis and reduces axon growth.
Axonal endogenous mechanism(s) to disassemble SGs
Proteins synthesized locally in axons are needed for PNS axon regeneration. Several lines of evidence indicate that injured spinal cord axons have the ability to synthesize proteins when they are made competent to regenerate.
Regenerating PNS axons have fewer G3BP1 granules than uninjured axons indicating that neurons have an endogenous mechanism(s) to disassemble axonal G3BP1 granules. Phosphorylation of the G3BP1 by Casein Kinase 2α (CK2α) has been associated with SG disassembly in other cellular systems. Though CK2α is known to be constitutively active, we showed that axonal CK2α activity is temporally and spatially restricted by on-demand translation of axonal Csnk2a1 mRNA after injury. CK2α appearance in axons after PNS nerve injury correlates with disassembly of axonal SGs and increased axon regeneration. Furthermore, we find that buffering the increased axoplasmic Ca²+ after injury provides a means for the axonal translational machinery to specifically switch between synthesis of proteins needed for injury response to those that promote axon growth like CK2α.
Targeting Axonal SGs to accelerate nerve regeneration
Our data show that G3BP1 protein inhibits axonal protein synthesis, which in turn attenuates axon regeneration, and blocking its function accelerates axon growth. While working on this project, we discovered a cell permeable peptide derived from the G3BP1 protein that acts as a dominant negative factor for endogenous G3BP1. This peptide also accelerates both PNS and CNS axon regeneration and prevents neurodegeneration (Sahoo et. al., Nat Comm, 2018, USA Patent # 10,668,128, USA Patent App # 16/881,096). Our most recent data show that the same mechanism also works in CNS axon growth. .