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

摘要 阿尔茨海默病（AD）是美国第六大死亡原因， 患者的寿命。除了痴呆，视觉障碍在AD患者中非常普遍， 严重影响其生活质量，引起行为挑战，甚至给AD患者带来安全风险。 与此同时，视力不佳是痴呆症的一个促成因素。然而，迄今为止，很少有研究 以解决AD中的视觉障碍。考虑到衰老是AD最著名的风险因素， 能够调节衰老过程的策略可能对AD的管理产生深远的影响。的一个主要 父母奖的重点是确定是否提高Sirt 6的表达，这是一个关键的抗衰老 分子，防止视网膜神经节细胞（RGC）中的线粒体功能障碍，从而保护视网膜免受 高眼压致小鼠青光眼模型RGC损伤及视神经变性 压力在本申请中，我们将进行实验以生成初步数据，以确定Sirt 6是否也 在AD中，通过抑制RGC及其轴突的损伤， 线粒体功能障碍未来，基于这项工作的试点数据，我们将进一步确定蜂窝 以及Sirt 6预防AD中RGC损伤和轴突变性的分子机制，以及 研究Sirt 6的药理学激活是否可以预防AD患者的视力丧失;此外，我们还将测试加强Sirt 6是否可以预防AD患者的视力丧失。 表达和活性加剧了AD期间大脑中的行为缺陷和神经变性， 视网膜是大脑的延伸，并且与大脑共享许多病理生理机制。总体而言，这 试点项目及其随后的未来研究将提供重要的新知识， 开发AD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.