Investigating Nerve Regeneration Following Traumatic Brain Injury( I )

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Rationale: Secondary axotomy/axon degeneration induced by TBI is considered as a key risk factor of the early onset of neurodegenerative diseases. Therefore, a detailed investigation of the mechanisms underlying TBI is thus important to identify effective treatments and improve the disease outcome. Preliminary Results and Hypothesis: We recently discovered that Znf179 acts as a novel neuroprotector and interacts with Sig-1R. After treatment with a Sig-1R agonist DHEAS, Znf179 increased its interaction with various cytoplasmic proteins, annotated to functions in “Protein Synthesis” and “Cellular Movement.” Moreover, we found an obvious localization of Znf179 on neurite growth cones (NGCs), and an increase in axonal outgrowth after Znf179 overexpression and DHEAS treatment. In addition, the tubulin deacetylase HDAC6 was also identified as a binding partner of Znf179. We thus suppose the following hypothesis: The HDAC6/Sig-1R/Znf179 pathway plays a pivotal role in axonal regeneration and functional recovery after traumatic axotomy. Specific Aim: First, we investigate whether local protein translation regulated by Znf179 is critical for the specification of neuronal polarity. Subsequently, we dissect the role of the Sig-1R/Znf179 pathway in NGC migration during axonal regeneration. Third, we examine whether HDAC6 regulates axonal regeneration by altering microtubule dynamics and Sig-1R/Znf179 interaction. Finally, potent regenerative agents targeting the HDAC6/Sig-1R/Znf179 pathway against TBI-induced neurodegeneration will be screened. Novelty and application: The role of Znf179 in neuronal axon regeneration after TBI remains unknown. By conducting this project as proposed, we will be able to verify that a pharmacological strategy-induced Znf179 functions via altering Sig-1R activation and HDAC signaling can facilitate intrinsic regenerative outgrowth after TBI.
StatusActive
Effective start/end date2/1/201/31/21

Keywords

  • Znf179
  • Sig-1R
  • HDAC6
  • TBI
  • Axonal regeneration