Anti-Aging Molecule Sirt6 in Neuroprotection in Diabetic Retina

抗衰老分子SIRT6在糖尿病视网膜神经保护中的作用 摘要 糖尿病视网膜病变(DR)是当今美国工作年龄成年人最常见的致盲原因。确实是 传统上以微血管并发症为特征，因为其临床表现为一段时期的血管 渗漏、变性和新生血管形成。然而，最近在动物模型和 已有研究表明，视网膜神经元损伤，尤其是视网膜神经节细胞(RGC)功能障碍和丢失， 发生在DR的早期阶段，并导致视力丧失。此外，尽管研究较少，但功能障碍和 糖尿病患者RGC轴突变性也很明显。DR靶点的当前治疗方法具有临床意义 血管渗漏或新生血管发生的时间要晚得多，对视网膜神经元没有保护作用。这 该项目旨在阐明DR期间RGC损伤和轴突变性的机制，以确定 限制伤害和保护视力的新策略。越来越多的证据表明，压力导致的早产 衰老(Sips)在许多疾病中起着关键作用。有几项研究报告了DR的sips，但他们 仅关注内皮细胞，并未将sips与DR病理联系起来。有一个重要的 关于DB如何在视网膜中诱导sip以及如何调节这种机制用于DR治疗的知识差距。 SIRT6是一种关键的抗衰老分子，属于在进化上保守的烟酰胺sirtuin家族。 依赖于腺嘌呤二核苷酸(NAD)的组蛋白脱乙酰酶，与酵母Sir2蛋白同源，a 酵母寿命的关键调节剂。我们现在建议检验一项假设，即SIRT6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)途径以防止 糖尿病视网膜病变中视网膜节细胞及其轴突的功能障碍/变性，部分是通过抑制视网膜节细胞的衰老和 线粒体功能障碍。我们将使用我们新开发的SIRT6全局和条件淘汰赛 (KO)/过表达小鼠，AAV2介导的基因敲除，临床相关非侵入性成像和 功能测试、免疫组织化学、生物化学和形态计量学分析来验证这一假设。这 研究将确定SIRT6和DDR-ATM通路在糖尿病视网膜病变和糖尿病视网膜病变中的新作用。 在它们之间建立一种联系。它还将提供概念验证，以增强抗衰老机制 可以用来治疗Dr。

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.