Anti-Aging Molecule Sirt6 in Neuroprotection in Diabetic Retina

抗衰老分子 Sirt6 对糖尿病视网膜神经保护作用

• 批准号: 10568150
• 负责人: Wenbo Zhang
• 金额: $ 54.19万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568150
• 关键词: ATM Signaling Pathway; Abbreviations; Acceleration; Adult; Age; Aging; Animal Model; Axon; Biochemistry; Blindness; Blood Vessels; Brain; Cardiovascular system; Cell Aging; Cell Death; Cell division; Cells; Cessation of life; Chronic; Clinic; Clinical; DNA Damage; DNA Repair; Data; Deacetylase; Diabetes Mellitus; Diabetic Retinopathy; Disease; Electroretinography; Endothelial Cells; Exhibits; Extravasation; Family; Functional disorder; Gamma-H2AX; Ganglion Cell Layer; Genes; Genomic Instability; Glucose; Histone Deacetylase; Histone H3; Homologous Gene; Immunohistochemistry; Inflammation; Injury; Inner Nuclear Layer; Kidney; Knock-out; Knowledge; Learning; Link; Longevity; Lysine; Mammals; Mediating; Microvascular Dysfunction; Mitochondria; Modeling; Mus; Nerve Degeneration; Neuronal Injury; Neurons; Nicotinamide adenine dinucleotide; Nuclear; Optic Nerve; Optical Coherence Tomography; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Positioning Attribute; Premature aging syndrome; Process; Proteins; Reperfusion Therapy; Reporting; Retina; Retinal Ganglion Cells; Role; Sirtuins; Stains; Stimulus; Streptozocin; Stress; Synapsins; Testing; Vision; Visual evoked cortical potential; Visual impairment; Yeasts; age related; anti aging; ataxia telangiectasia mutated protein; axon injury; axonal degeneration; beta-Galactosidase; blood glucose regulation; cell injury; cell type; clinically significant; conditional knockout; diabetic; gene repression; knock-down; member; mitochondrial dysfunction; mouse model; neovascularization; neuroprotection; nitrosative stress; non-invasive imaging; novel; novel strategies; overexpression; premature; preservation; prevent; response; retinal ganglion cell degeneration; retinal ischemia; retinal neuron; senescence; transcription factor

Anti-Aging Molecule Sirt6 in Neuroprotection in Diabetic Retina SUMMARY Diabetic retinopathy (DR) is the most frequent cause of blindness in working age adults in the US today. It was traditionally characterized as microvascular complications due to its clinical manifestation of a period of vascular leakage and degeneration followed by neovascularization. However, recent studies in animal models and patients have shown that retinal neuron injury, in particular retinal ganglion cell (RGC) dysfunction and loss, occurs at early stage of DR and contributes to vision loss. Moreover, though less studies, dysfunction and degeneration of axons of RGC is also evident in diabetes. Current therapies for DR targets clinically significant vascular leakage or neovascularization, which happens much later, and do not protect retinal neurons. This project is to delineate the mechanisms of RGC injury and axonal degeneration during DR in order to identify novel strategies to limit injury and preserve vision. Increasing evidence indicates that stress-induced premature senescence (SIPS) plays a key role in many diseases. There are a few studies reporting SIPS in DR but they are exclusively focused on endothelial cells and have not linked SIPS to DR pathology. There is a significant knowledge gap on how Db induce SIPS in the retina and how to regulate such mechanisms for DR treatment. Sirt6 is a key anti-aging molecule belonging to the sirtuin family that is evolutionarily conserved nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and shares homolog with yeast Sir2 protein, a critical regulator of the lifespan of yeast. We now propose to test a hypothesis that Sirt6 suppresses chronic activation of the DNA damage response (DDR)-ATM (ataxia-telangiectasia mutated) pathway to prevent dysfunction/degeneration of RGCs and their axons in DR, partly by inhibiting RGC senescence and mitochondrial dysfunction. We will use our newly developed Sirt6 global and conditional knockout (KO)/overexpression mice, AAV2-mediated gene knockdown, clinic-relevant non-invasive imaging and functional tests, immunohistochemistry, biochemistry and morphometric analyses to test this hypothesis. This study will identify novel roles of Sirt6 and DDR-ATM pathway in RGC and axonal degeneration in DR and establish a link between these them. It will also provide proof-of-concept that boosting anti-aging mechanisms may be utilized to treat DR.

抗衰老分子Sirt 6在糖尿病视网膜神经保护中的作用 总结 糖尿病视网膜病变（DR）是当今美国工作年龄成人失明的最常见原因。这是 传统上以微血管并发症为特征，由于其临床表现为一段时间的血管病变， 渗漏和变性，随后是新血管形成。然而，最近在动物模型和 患者已经表明，视网膜神经元损伤，特别是视网膜神经节细胞（RGC）功能障碍和丧失， 发生在DR的早期阶段，并导致视力丧失。此外，虽然研究较少，但功能障碍和 RGC轴突的变性在糖尿病中也是明显的。DR靶点的当前治疗具有临床意义 血管渗漏或新血管形成，这发生得更晚，并且不保护视网膜神经元。这 本研究旨在阐明DR过程中RGC损伤和轴突变性的机制， 限制损伤和保护视力的新策略。越来越多的证据表明，应激诱导的早产儿 衰老（SIPS）在许多疾病中起关键作用。有一些研究报告了DR中的SIPS，但它们 仅关注内皮细胞，没有将SIPS与DR病理联系起来。存在显著 关于Db如何在视网膜中诱导SIPS以及如何调节这种机制用于DR治疗的知识缺口。 Sirt 6是一种关键的抗衰老分子，属于sirtuin家族，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，与酵母Sir 2蛋白有同源性， 酵母寿命的关键调节剂。我们现在提出测试一个假设，即Sirt 6抑制慢性 激活DNA损伤反应（DDR）-ATM（共济失调-毛细血管扩张突变）途径， DR中RGC及其轴突的功能障碍/变性，部分通过抑制RGC衰老， 线粒体功能障碍我们将使用我们新开发的Sirt 6全局和条件敲除 (KO)/过表达小鼠，AAV 2介导的基因敲减，临床相关的非侵入性成像和 功能测试、免疫组织化学、生物化学和形态测定分析来检验这一假设。这 研究将确定Sirt 6和DDR-ATM通路在RGC和DR轴突变性中的新作用， 在它们之间建立联系。它还将提供增强抗衰老机制的概念验证 可用于治疗DR。