AD-focused Administrative Supplement for NIH Grant Neuroprotective Role of Sirt6 in Glaucoma

摘要 阿尔茨海默病(AD)是美国第六大主要死因，它显著损害了 病人的寿命。除了痴呆症，视力障碍在AD患者中非常普遍， 严重影响他们的生活质量，造成行为挑战，甚至给AD患者带来安全风险。 与此同时，视力不佳是导致痴呆症的一个因素。然而，到目前为止，很少有研究是 旨在解决AD患者的视觉障碍问题。考虑到衰老是阿尔茨海默病最众所周知的风险因素， 可以调节衰老过程的策略可能会对AD的管理产生深远的影响。其中一个主要的 家长奖的重点是确定是否促进SIRT6的表达，这是一种关键的抗衰老 分子，防止视网膜神经节细胞(RGC)线粒体功能障碍，从而保护 高眼压致小鼠青光眼模型视网膜中央皮质损伤及视神经变性 压力。在此应用程序中，我们将进行实验以生成初步数据，以确定SIRT6是否也 对阿尔茨海默病视网膜节细胞及其轴突损伤的神经保护作用 线粒体功能障碍。未来，我们将根据这项工作的试点数据，进一步确定蜂窝 以及SIRT6预防AD大鼠RGC损伤和轴突变性的分子机制 研究SIRT6的药理激活是否能防止AD患者的视力丧失；此外，我们还将测试是否促进SIRT6 表达和活动可以缓解AD期间大脑中的行为缺陷和神经退化，因为 视网膜是大脑的延伸，与大脑有许多共同的病理生理机制。总体而言，这 试点项目及其后续研究将提供重要的新知识，可指导 开发阿尔茨海默病的新疗法。

ABSTRACT Alzheimer's disease (AD) is the sixth-leading cause of death in the United States that significantly impairs patients' lifespan. In addition to dementia, visual impairments are very prevalent in AD patients and significantly affect their life quality, cause behavioral challenges and even put safety risks to AD patients. Meanwhile, poor vision is a contributing factor to dementia. Nevertheless, to date, few studies have been conducted to address visual impairments in AD. Considering aging is the best known risk factor for AD, strategies that can modulate aging process may have profound effects for AD management. One of the major focuses in the parent award is to determine whether boosting expression of Sirt6, which is a key anti-aging molecule, prevents mitochondrial dysfunction in retinal ganglion cells (RGCs) and therefore protects against RGC injury and optic nerve degeneration in mouse models of glaucoma induced by elevated intraocular pressure. In this application, we will conduct experiments to generate preliminary data to determine if Sirt6 also plays a neuroprotective role in preventing the injury of RGCs and their axons in AD via inhibition of mitochondrial dysfunction. In the future, based on pilot data from this work, we will further determine cellular and molecular mechanisms by which Sirt6 prevents RGC injury and axonal degeneration in AD, and investigate if pharmacologic activation of Sirt6 prevents vision loss in AD; moreover, we will test if boosting Sirt6 expression and activity alleviates behavioral deficits and neurodegeneration in the brain during AD, given that the retina is an extension of the brain and shares many pathophysiological mechanisms of the brain. Overall, this pilot project and its subsequent future studies will provide important new knowledge that may guide the development of novel therapies for AD.