Deciphering the Transcriptional Regulatory Network Controlling RGC Axon Growth to Promote RGC Axon Regeneration and Cell Survival after Axonal Injury

破译控制 RGC 轴突生长的转录调控网络,以促进轴突损伤后 RGC 轴突再生和细胞存活

基本信息

  • 批准号:
    10222710
  • 负责人:
  • 金额:
    $ 10.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

Project Summary In the past decade, restoring the intrinsic axon growth ability of mature neurons has received promising results in promoting axon regeneration in the central nervous system (CNS). However, to date, axon regeneration that leads to successful functional recovery in the CNS is still practically impossible, primarily due to the inadequate distance of regeneration and the low number of regenerating axons. Previous studies and my preliminary data have shown that many genes mediating the intrinsic axon growth ability are differentially expressed at different developmental stages in neurons, indicating the altered gene expression level during neuronal maturation is an important factor underlying the diminished intrinsic axon growth capacity. However, how the altered gene expression program is regulated remains largely unknown. Transcription factors (TFs) play important roles during neuronal development, shaping the spatiotemporal gene expression landscape to control cellular activities including axon elongation. Thus, understanding the intricate transcriptional regulatory network orchestrating axon growth during development is critical for solving the challenge of mammalian CNS axon regeneration. In this proposed study, I will perform parallel RNA-seq and ATAC-seq of purified retinal ganglion cells (RGCs) at multiple developmental time points, and use advanced integrative bioinformatics analysis to obtain a comprehensive view of the transcriptional regulatory network controlling the axon elongation function during RGC development, and identify key TFs that function as core regulators of axon growth. The identified TFs will be functionally tested in mouse optic nerve regeneration model to verify if they play important roles in RGC axon regeneration and cell survival. RGCs are comprised of more than forty molecular distinct subtypes. Different RGC subtypes vary in vulnerability to axonal injury and have distinct responses toward gene modulations. I will conduct single-cell RNA-seq (scRNA-seq) in RGCs 2 weeks after optic nerve crush from control and TF- manipulated groups to acquire the frequency of each RGC subtype in the final population, and determine what specific RGC subtypes are protected by the manipulation of a specific TF by comparing the frequencies of RGC subtypes between control and TF-manipulated groups. TFs whose manipulations are found to improve survival in distinct RGC subtypes will be combined in the next step to determine if simultaneously manipulating these TFs could protect a wide variety of RGC subtypes from injury-induced cell death and induce synergistic promoting effect on RGC axon regeneration. In addition, I will also combine the manipulations of these TFs with non-muscle myosin IIA/B deletion in RGCs, which produces axon regeneration by modifying cytoskeletal dynamics in the growth cone of injured axons, to find out if this combinatory approach could lead to unprecedented long-distance axon regeneration.

项目成果

期刊论文数量(0)
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Xuewei Wang其他文献

Xuewei Wang的其他文献

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{{ truncateString('Xuewei Wang', 18)}}的其他基金

Antibacterial and Antithrombotic Catheter Lock Solutions Based on Controlled Release of Nitric Oxide
基于一氧化氮控制释放的抗菌和抗血栓导管锁解决方案
  • 批准号:
    10634183
  • 财政年份:
    2023
  • 资助金额:
    $ 10.58万
  • 项目类别:
Self-calibrated ionophore-based ion-selective electrodes for at-home measurements of blood electrolytes
用于家庭测量血液电解质的自校准离子载体离子选择电极
  • 批准号:
    10592523
  • 财政年份:
    2023
  • 资助金额:
    $ 10.58万
  • 项目类别:
Deciphering the Transcriptional Regulatory Network Controlling RGC Axon Growth to Promote RGC Axon Regeneration and Cell Survival after Axonal Injury
破译控制 RGC 轴突生长的转录调控网络,以促进轴突损伤后 RGC 轴突再生和细胞存活
  • 批准号:
    10805158
  • 财政年份:
    2020
  • 资助金额:
    $ 10.58万
  • 项目类别:
Deciphering the Transcriptional Regulatory Network Controlling RGC Axon Growth to Promote RGC Axon Regeneration and Cell Survival after Axonal Injury
破译控制 RGC 轴突生长的转录调控网络,以促进轴突损伤后 RGC 轴突再生和细胞存活
  • 批准号:
    10680357
  • 财政年份:
    2020
  • 资助金额:
    $ 10.58万
  • 项目类别:
Deciphering the Transcriptional Regulatory Network Controlling RGC Axon Growth to Promote RGC Axon Regeneration and Cell Survival after Axonal Injury
破译控制 RGC 轴突生长的转录调控网络,以促进轴突损伤后 RGC 轴突再生和细胞存活
  • 批准号:
    10038926
  • 财政年份:
    2020
  • 资助金额:
    $ 10.58万
  • 项目类别:

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