Develop a novel regenerative therapy
Funded in: 2021, 2022, 2023
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Problem: Neurons in the central nervous system lose the ability to regenerate axons with age
Target: ZNF362, a transcription factor that controls age-dependent loss of neuronal growth capacity
Goal: Identifying a new target for enhancing axon regeneration
Treatments to reverse paralysis after spinal cord injury (SCI) are not available and people who have suffered SCI are permanently disabled. Neurons in the central nervous system (CNS) lose the ability to regenerate axons with age, and this limits functional recovery after CNS injury.
Many genes have been determined to control the growth ability of mature neurons, but none have been translated to clinical use. There is a persistent need to identify better targets and improved delivery methods. The best targets are probably those with the potential to impact multiple genes simultaneously. The neuroscientists hypothesize that ZNF362, a transcription factor downstream of let-7 miRNA, controls the age-dependent loss of neuronal growth capacity in adult CNS and that its inhibition stimulates robust nerve regeneration and functional recovery after SCI by targeting various genes. Their lab generated conditional knockout (cKO) mice as a genetic tool to study function of ZNF362 in mammals and designed the sequence-targeting peptides that block ZNF362 function selectively.
Firstly, the researchers will study whether deleting ZNF362 promotes dramatic regrowth of multiple descending tracts and recovery in adult cKO mice with SCI. Importantly, the neuroscientists will determine whether ZNF362 antagonist peptides promote in vivo nerve regrowth and functional recovery in adult mice with transection SCI, aiming to select the optimal peptides.
The second aim will be to validate the efficiency of the top two optimal ZNF362 peptides in promoting robust regrowth of motor tracts and recovery in adult mice with contusion SCI, a model mimicking the lesions of many SCI patients, when delivered several days or weeks after SCI. Based on their promising results of the pilot study, they anticipate that their novel peptide antagonists will significantly advance the ability to treat SCI. Therefore, this project should facilitate identifying a new target for enhancing CNS axon regeneration and effective therapies for SCI.