中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (3): 629-635.doi: 10.4103/1673-5374.380907

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury

  

  • 出版日期:2024-03-15 发布日期:2023-09-02

Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury

Jingzhou Liu1, Xin Xin1, Jiejie Sun1, Yueyue Fan2, Xun Zhou1, Wei Gong1, Meiyan Yang1, Zhiping Li1, Yuli Wang1, Yang Yang1, *, #br# Chunsheng Gao1, *#br#   

  1. 1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China; 2Academy of Medical Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
  • Online:2024-03-15 Published:2023-09-02
  • Contact: Yang Yang, PhD, amms2013@126.com; Chunsheng Gao, PhD, gaocs@bmi.ac.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 82073783 (to YY) and the Natural Science Foundation of Beijing, No. 7212160 (to YY).

摘要:

创伤性脑损伤可导致神经元丢失和胶质瘢痕形成,因此,补充丢失神经元和消除胶质瘢痕对于创伤性脑损伤的治疗至关重要。神经元重编程是将胶质瘢痕转化为神经组织的一个有希望的策略。然而,目前尚未得到一致的研究结果。实验使用了包括星形细胞靶向P1肽和胶质纤维酸性蛋白原聚体的AAV9P1载体来实现星形细胞和胶质瘢痕的双靶向,同时最大限度地减少脱靶效应。结果表明,AAV9P1对星形胶质细胞和反应性星形胶质细胞具有高选择性。此外,在创伤性脑损伤小鼠模型中,AAV9P1的全身给药可下调多嘧啶束结合蛋白1基因表达来诱导神经元重编程。总之,这种方法为研究神经元编程提供了一个更好的基因递送载体,并为其在创伤性脑损伤中的应用提供了更多证据。

https://orcid.org/0000-0002-3195-2069 (Yang Yang); https://orcid.org/0000-0002-5542-1561 (Chunsheng Gao)

Abstract: Traumatic brain injury results in neuronal loss and glial scar formation. Replenishing neurons and eliminating the consequences of glial scar formation are essential for treating traumatic brain injury. Neuronal reprogramming is a promising strategy to convert glial scars to neural tissue. However, previous studies have reported inconsistent results. In this study, an AAV9P1 vector incorporating an astrocyte-targeting P1 peptide and glial fibrillary acidic protein promoter was used to achieve dual-targeting of astrocytes and the glial scar while minimizing off-target effects. The results demonstrate that AAV9P1 provides high selectivity of astrocytes and reactive astrocytes. Moreover, neuronal reprogramming was induced by downregulating the polypyrimidine tract-binding protein 1 gene via systemic administration of AAV9P1 in a mouse model of traumatic brain injury. In summary, this approach provides an improved gene delivery vehicle to study neuronal programming and evidence of its applications for traumatic brain injury.

Key words: AAV9P1, astrocytes, astrocyte-to-neuron conversion, GFAP promoter, glial scar, induced neurons, neuronal reprogramming, P1 peptide, PTBP1, traumatic brain injury