Neuroprotective Role of Sirt6 in Glaucoma

Sirt6 在青光眼中的神经保护作用

基本信息

批准号：
10193762
负责人：
Hua Liu
金额：
$ 7.51万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10193762
关键词：
Age Aging Axon Blindness Cell Death Cell Survival Cell physiology Clinic DNA Repair Deacetylase Development Functional disorder Genes Genetic Genetic Transcription Genomic Instability Glaucoma Histone Deacetylase Histone H3 Homologous Gene Image Inflammation Injury Knowledge Longevity Lysine Mediating Molecular Biology Techniques Mus Nerve Degeneration Neuropathy Neurosciences Nicotinamide adenine dinucleotide Optic Nerve Pathologic Physiologic Intraocular Pressure Physiology Play Positioning Attribute Predisposition Prevention Process Proteins Publications Research Priority Retina Retinal Ganglion Cells Risk Factors Role Series Sirtuins Testing Therapeutic Intervention Vision research Yeasts anti aging axon regeneration blood glucose regulation cell injury conditional knockout knock-down member neuroprotection non-invasive imaging novel strategies novel therapeutics overexpression prevent retinal ganglion cell degeneration transcription factor

项目摘要

Project title: Neuroprotective Role of Sirt6 in Glaucoma SUMMARY Glaucoma is the second leading cause of irreversible blindness worldwide. It is characterized as progressive retinal ganglion cell (RGC) death and optic nerve degeneration. Strong risk factors for glaucoma include elevated intraocular pressure (IOP), age and genetic background. Among them, only IOP is well-studied and serves as the only treatable target for glaucoma. However, lowering IOP does not always stop the progression of glaucoma. It is urgent to identify other mechanisms of neuropathy in glaucoma for therapeutic intervention. Sirtuin (Sirt) 6 is a member of the Sirts that are evolutionarily conserved nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and share homolog with yeast Sir2 protein that critically regulates lifespan of yeast. It is a histone H3 lysine 9 (H3K9) and H3K56 deacetylase which represses the transcription activities of several transcription factors involved in aging and inflammation, promotes DNA repair, prevents genomic instability and maintains glucose homeostasis. These multiple functions of Sirt6 position it as a key anti-aging molecule. Sirt6 is expressed in the retina but its role in glaucoma is unknown. This application will integrate a series of novel approaches including our newly developed Sirt6 global and conditional knockout /overexpression mice, AAV2-mediated gene knockdown, clinic-relevant non-invasive imaging and functional tests, state-of-the-art imaging to test the hypothesis that Sirt6 plays a key role in the prevention of dysfunction/degeneration of retinal ganglion cells and their axons in glaucoma. We will: 1) test the hypothesis that loss of Sirt6 causes pathological changes in the retina and optic nerve resembling glaucoma; 2) test the hypothesis that boosting Sirt6 expression prevents pathological changes in the retina and optic nerve in IOP elevation-induced glaucoma. Completion of the proposed studies will provide important new knowledge that may guide the development of novel therapies for glaucoma. This proposal is in line with vision research priorities identified in the NEI Publication, “Vision Research: Needs, Gaps, & Opportunities”: 1) Determine the mechanisms by which risk factors, such as age and prior glaucomatous injury, influence susceptibility of remaining RGC axons to elevated IOP; 2) Apply molecular biology techniques to RGC neuroscience to dissect factors important for survival, axon regeneration, and physiology; 3) Explore neuroprotection as an approach for prolonging RGC function and survival.

项目名称：Sirt6 在青光眼中的神经保护作用概括青光眼是全球不可逆性失明的第二大原因，其特点是进行性。视网膜神经节细胞（RGC）死亡和视神经变性是青光眼的重要危险因素。眼压升高（IOP）、年龄和遗传背景其中，只有IOP得到了充分研究和研究。然而，降低眼压并不总能阻止青光眼的进展。迫切需要确定青光眼神经病变的其他机制以进行治疗干预。 Sirtuin (Sirt) 6 是 Sirts 的成员，是进化上保守的烟酰胺腺嘌呤二核苷酸 (NAD) 依赖性组蛋白脱乙酰酶，与关键调控的酵母 Sir2 蛋白具有同源性它是抑制转录的组蛋白 H3 赖氨酸 9 (H3K9) 和 H3K56 脱乙酰酶。参与衰老和炎症的多种转录因子的活性，促进 DNA 修复，预防 Sirt6 的这些多重功能使其成为关键。 Sirt6 在视网膜中表达，但其在青光眼中的作用尚不清楚。整合了一系列新颖的方法，包括我们新开发的 Sirt6 全局和条件敲除 /过表达小鼠，AAV2介导的基因敲除，临床相关的非侵入性成像和功能测试，最先进的成像来测试 Sirt6 在预防中发挥关键作用的假设青光眼中视网膜神经节细胞及其轴突的功能障碍/变性我们将：1）测试假设 Sirt6 缺失会导致视网膜和视神经发生类似于青光眼的病理变化； 2) 检验增强 Sirt6 表达可预防视网膜和视神经病理变化的假设神经眼压升高引起的青光眼的研究的完成将提供重要的新成果。可能指导青光眼新疗法开发的知识该提议符合愿景。 NEI 出版物“视觉研究：需求、差距和机遇”中确定的研究重点：1) 确定风险因素（例如年龄和既往青光眼损伤）影响的机制剩余 RGC 轴突对 IOP 升高的敏感性 2) 将分子生物学技术应用于 RGC；神经科学剖析对生存、轴突再生和生理学重要的因素 3) 探索神经保护作为延长 RGC 功能和生存的一种方法。