Sirt1通路在视神经变性损伤中的作用机制研究

Axonal injury occurs in many neurologic diseases, such as Alzheimer disease and multiple sclerosis (MS), and is considered a predictor of progressive neuron degeneration. A common feature of neurodegenerative diseases is the irreversible loss of neurons by activation of apoptosis. Numerous molecules involved in the promotion or inhibition of neuronal apoptosis have been identified. In optic neuropathy such as glaucoma, recent studies (including applicant) have suggested that damage to optic nerve axon and visual pathway may precede retinal ganglion cell (RGC) body loss. Apoptosis pathway is activated in RGC axon degeneration in glaucoma. Sirt1 is a group of deacetylase enzymes that are involved in variety of cellular functions, including stress response, DNA repair, neuronal survival and axonal degeneration. The goal of this proposal is to better understand the role of SIRT1 in the regulation of retinal neuron survival. We hypothesize that regulation of Sirt1 activation in retinal neuron and axon through caspases (caspase3 for RGC death, caspase6 for axonal degeneration) pathway which contributes to RGC axon degeneration/regeneration in optic neuropathy. The following specific aims will address the above hypothesis: 1) Determine Sirts activation and expression in retinas and optic nerve axons following RGC axon injury, 2) Determine downstream targets and mechanism of SIRT1 action in RGCs and their axons, and 3) Determine Resveratrol , a Sirts activator is neuroprotecctive for RGC axons in glaucoma models. The proposed studies would shed insight into how SIRT1 exerts its neuroprotective effect and provide novel strategies to prevent neuronal loss in neurodegenerative diseases.

神经退行性疾病有一个共同特点是通过激活细胞凋亡导致神经元异常和过度的损失。在视觉系统表现为不可逆视力损失如青光眼和多发性硬化症。我们通过近期研究的结果提出了青光眼"dying-back degeneration（逆行变性）" 学说。我们发现在动物模型中视神经轴突和视觉通路的损害变性先于视网膜神经节细胞（RGC）胞体的损失。我们拟在本课题中进一步探讨青光眼"Axonopathy（轴突病变）"机制。SIRT1是一组脱乙酰基酶，参与多种细胞功能，包括神经元的存活和轴突变性。我们的假设是：视网膜神经节细胞和轴突SIRT1活性调节其下游caspases活性而参与神经轴突变性/再生。我们拟用视神经损伤动物模型探讨SIRT1的作用机制和明确是否Sirt1激活剂和拮抗剂影响RGC生存和神经轴突变性再生。本项目研究将揭示SIRT1介导视神经变性的作用机理，为神经变性性疾病的治疗提供一种新的思路。

神经视网膜衰老变性疾病如青光眼（glaucoma）、老年黄斑变性（AMD）等严重影响人类健康，目前对这类疾病缺乏有效治疗手段，原因在于疾病相关的机制不明。本项目聚焦在Sirtuin家族，通过使用视网膜损伤变性的动物模型和不同种属（人和动物）的视网膜组织，以及分子生物学方法及免疫组织化学方法，我们探讨了视网膜变性过程和Sirtuin的关系。我们发现Sirtuin在不同种属的视网膜有广泛的表达，且具有重要的不同的生理功能，sirt1激动剂白藜芦醇有明显的抗视网膜衰老和变性的作用，sirt3，sirt4 和sirt5作为线粒体相关酶在调节视网膜神经变性方面具有重要作用。我们的结果也发现sirt1活性增加可调节caspase3/6介导的视网膜及轴突变性。在课题基金的资助下，本项目研究对明确SIRTs介导视神经变性的作用机理有了更新的认识，为神经变性性疾病的治疗提供一种新的靶点和思路。