Visual Research Project
Development of Therapeutic Strategies for Visual Impairment using Neuroprotection and Optic Nerve Regeneration
Achievements in 2024
Neurotrophic factor signaling holds significant promise as therapeutic target for neuroprotection and optic nerve regeneration. However, the temporal efficacy of ligand-mediated activation remains limited. To address this challenge, we developed a novel gene therapy approach that utilizes forced membrane translocation of the intracellular domain of tropomyosin receptor kinase B (iTrkB), a receptor for brain-derived neurotrophic factor (BDNF). The system enabled us to achieve notable neuroprotection in an experimental glaucoma model. Furthermore, we observed robust axon regeneration following optic nerve injury in response to iTrkB expression (Nishijima et al., 2023).
Insulin, a key endocrine hormone regulating glucose homeostasis, also plays a crucial role in brain function. Accumulating evidence indicates that impaired insulin signaling is associated with cognitive decline and neurodegenerative diseases. While recent studies have suggested that insulin can stimulate dendrite regeneration in retinal ganglion cells (RGCs), a neuronal population vulnerable in glaucoma, ligand-mediated activation has limitations in terms of sustained efficacy. Inspired by the iTrkB system, we developed constitutively active forms of the insulin receptor and insulin-like growth factor receptor. We achieved in activating downstream signaling pathways implicated in dendrite regeneration in vitro (Sotozono et al., 2024). These novel tools hold promise for neuroprotection and promoting dendrite regeneration in various neuronal populations.
Publications
Papers in 2024
- Sotozono A, Namekata K, Guo X, Shinozaki Y, Harada C, Noro T, Nakano T, Harada T (2024) “Membrane-anchored intracellular insulin receptor or insulin-like growth factor-1 receptor elicits ligand-independent downstream signaling.” Biochemistry and Biophysics Reports 39, 101799.
- Namekata K, Noro T, Nishijima E, Sotozono A, Guo X, Harada C, Shinozaki Y, Mitamura Y, Nakano T, Harada T (2024) “Drug combination of topical ripasudil and brimonidine enhances neuroprotection in a mouse model of optic nerve injury.” Journal of Pharmacological Sciences 154, 326-333.
- Wang Y, Brahma MM, Takahashi K, Hernandez ANB, Ichikawa K, Minami S, Goshima Y, Harada T, Ohshima T (2024) “Drug treatment attenuates retinal ganglion cell death by inhibiting collapsin response mediator protein 2 phosphorylation in mouse models of normal tension glaucoma.” Neuromolecular Medicine 26, 13
- Shinozaki Y, Namekata K, Guo X, Harada T (2024) “Glial cells as a promising therapeutic target of glaucoma: beyond the IOP.” Frontiers in Ophthalmology 3, 1310226.
Key Papers
- Nishijima E, Honda S, Kitamura Y, Namekata K, Kimura A, Guo X, Azuchi Y, Harada C, Murakami A, Matsuda A, Nakano T, Parada LF, Harada T (2023) “Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors." Molecular Therapy 31(3), 810-824.
- Guo X, Kimura A, Namekata K, Harada C, Arai N, Takeda K, Ichijo H, Harada T (2022) “ASK1 signaling regulates phase-specific glial interactions during neuroinflammation.” PNAS 119(6), e2103812119.