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首页> 外文学位 >Role of the ASPP Family in the Regulation of p53-Mediated Apoptotic Death of Retinal Ganglion Cells after Optic Nerve Injury.
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Role of the ASPP Family in the Regulation of p53-Mediated Apoptotic Death of Retinal Ganglion Cells after Optic Nerve Injury.

机译：ASPP家族在视神经损伤后调节p53介导的视网膜神经节细胞凋亡死亡中的作用。

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摘要

Glaucoma is the leading cause of irreversible blindness worldwide. At present, there is no cure for glaucoma, and current therapies are often inadequate. Loss of vision in glaucoma results from the death of retinal ganglion cells, the neurons that send visual information from the retina to the brain. The principal mechanism leading to retinal ganglion cell damage during glaucoma is not well understood, however, putative culprits have been proposed including excitotoxicity, neurotrophin deprivation, mechanical compression, ischemia, reactive astrocytes and oxidative stress. It is well established that retinal ganglion cell loss during glaucoma is caused by apoptotic programmed cell death, however, the precise mechanisms that lead to apoptotic death of adult retinal ganglion cells are poorly defined. To address this point, I put forth the central hypothesis that the identification of signaling pathways involved in apoptotic retinal ganglion cell death would offer therapeutic avenues to slow or prevent retinal ganglion cell death during ocular neuropathies such as glaucoma.;In the first part of my thesis, I characterised the role of Apoptosis Stimulating Protein of p53 family (ASPP) proteins, which are regulators of p53, in the apoptotic death of retinal ganglion cells. p53 is a nuclear transcription factor implicated in cellular functions ranging from transcription to apoptosis. ASPP family members ASPP1, ASPP2 and iASPP are p53 binding proteins that belong to a family of protein regulators of p53-dependent apoptotic death. However, the role of ASPP family members in retinal ganglion cell death is unknown. As ASPP1 and ASPP2 are pro-apoptotic, the hypothesis of our first study was that the knockdown of ASPP1 and ASPP2 gene expression would lead to retinal ganglion cell survival after an optic nerve lesion. We used a well-characterized experimental model of neuronal apoptosis induced by optic nerve axotomy in Sprague Dawley rats. The results of this study (Wilson et al. Journal of Neuroscience, 2013) demonstrated that p53 is implicated in retinal ganglion cell death, and that targeted knockdown of ASPP1 and ASPP2 by short interference ribonucleic acid promotes retinal ganglion cell survival. The knockdown of ASPP2 correlates with a reduction in the levels of pro-apoptotic p53 regulated targets PUMA and Fas/CD95.;In the second part of my thesis, I characterized the role of the anti-apoptotic member of the ASPP family, iASPP, in the apoptotic death of retinal ganglion cells. The hypothesis of this second study is that the overexpression of iASPP would promote retinal ganglion cell survival after axotomy. The data (Wilson et al. PLoS ONE, 2014) demonstrate that the targeted knockdown of iASPP by short interference ribonucleic acid exacerbates retinal ganglion cell death, and that the overexpression of iASPP by adeno-associated virus promotes retinal ganglion cell survival. The overexpression of iASPP correlates with a reduction in protein levels of PUMA and Fas/CD95.;In conclusion, the findings presented in this thesis contribute to a better understanding of the pathological mechanisms underlying retinal ganglion cell loss by apoptosis and might provide insights into the design of novel neuroprotective treatments for neurodegenerative diseases such as glaucoma.;Key words: retinal ganglion cell, neuronal death, apoptosis-stimulating protein of p53, axotomy.
机译：青光眼是全球不可逆失明的主要原因。目前，尚无可治愈的青光眼，并且当前的疗法常常是不足的。青光眼的视力丧失是由视网膜神经节细胞的死亡造成的，视网膜神经节细胞是从视网膜向大脑发送视觉信息的神经元。导致青光眼期间视网膜神经节细胞损伤的主要机制尚不清楚，但是，已经提出了推测的罪魁祸首，包括兴奋性毒性，神经营养蛋白剥夺，机械压迫，局部缺血，反应性星形胶质细胞和氧化应激。众所周知，青光眼期间视网膜神经节细胞的丧失是由程序性细胞死亡引起的，然而，导致成年视网膜神经节细胞凋亡性死亡的确切机制尚不清楚。为了解决这一点，我提出了一个中心假设，即与凋亡性视网膜神经节细胞死亡有关的信号通路的识别将为减缓或预防眼神经病如青光眼期间视网膜神经节细胞死亡提供治疗途径。论文中，我描述了p53家族的凋亡刺激蛋白p53家族（ASPP）在视网膜神经节细胞凋亡中的作用。 p53是一种涉及细胞功能的核转录因子，涉及从转录到凋亡的各种功能。 ASPP家族成员ASPP1，ASPP2和iASPP是p53结合蛋白，属于p53依赖性凋亡死亡的蛋白调节剂家族。但是，ASPP家族成员在视网膜神经节细胞死亡中的作用尚不清楚。由于ASPP1和ASPP​​2具有促凋亡作用，因此我们的第一项研究的假设是，敲低ASPP1和ASPP​​2基因表达将导致视神经病变后视网膜神经节细胞的存活。我们使用了特征丰富的实验模型，该模型由视神经轴突切开术在Sprague Dawley大鼠中诱导神经元凋亡。这项研究的结果（Wilson等人，《神经科学杂志》，2013年）证明，p53与视网膜神经节细胞死亡有关，并且通过短暂干扰核糖核酸靶向敲除ASPP1和ASPP​​2可以促进视网膜神经节细胞存活。 ASPP2的敲低与促凋亡的p53调控靶标PUMA和Fas / CD95的降低有关。在论文的第二部分中，我描述了ASPP家族抗凋亡成员iASPP的作用，在视网膜神经节细胞的凋亡死亡中。第二项研究的假设是，iASPP的过表达将促进轴突切开术后视网膜神经节细胞的存活。数据（Wilson et al.PLoS ONE，2014）证明，短干扰核糖核酸对iASPP的靶向敲除会加剧视网膜神经节细胞的死亡，而腺相关病毒过度表达iASPP会促进视网膜神经节细胞的存活。 iASPP的过表达与PUMA和Fas / CD95的蛋白水平降低有关。总之，本论文提出的发现有助于更好地了解凋亡引起的视网膜神经节细胞丧失的病理机制，并可能为深入了解该现象提供参考。关键词：视网膜神经节细胞，神经元死亡，p53细胞凋亡刺激蛋白，轴突切开术

著录项

  • 作者

    Wilson, Ariel.;

  • 作者单位

    Universite de Montreal (Canada).;

  • 授予单位 Universite de Montreal (Canada).;
  • 学科 Biology Cell.;Health Sciences Ophthalmology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 198 p.
  • 总页数 198
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

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