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

NIH 以 AD 为重点的行政补充授予 Sirt6 在青光眼中的神经保护作用

• 批准号: 10289439
• 负责人: Hua Liu
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10289439
• 关键词: Address; Administrative Supplement; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Award; Axon; Behavioral; Blindness; Brain; Cause of Death; Data; Deacetylase; Dementia; Development; Disease Management; Future; Glaucoma; Grant; Histone H3; Impairment; Injury; Knowledge; Longevity; Lysine; Molecular; Nerve Degeneration; Optic Nerve; Parents; Patients; Pharmacology; Physiologic Intraocular Pressure; Pilot Projects; Play; Process; Quality of life; Retina; Retinal Ganglion Cells; Risk; Role; Safety; Testing; United States; United States National Institutes of Health; Vision; Visual impairment; Work; anti aging; axonal degeneration; base; cell injury; experimental study; mitochondrial dysfunction; mouse model; novel therapeutics; prevent

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.

抽象的 阿尔茨海默病 (AD) 是美国第六大死因，严重损害人们的健康 患者的寿命。除了痴呆症外，AD 患者还普遍存在视力障碍 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，迄今为止，还很少有研究 旨在解决 AD 中的视觉障碍问题。考虑到衰老是 AD 最著名的危险因素， 能够调节衰老过程的策略可能会对 AD 管理产生深远的影响。主要之一 家长奖的重点是确定是否增强Sirt6的表达，Sirt6是抗衰老的关键 分子，防止视网膜神经节细胞（RGC）线粒体功能障碍，从而防止 眼压升高致小鼠青光眼模型RGC损伤及视神经变性 压力。在此应用中，我们将进行实验来生成初步数据，以确定 Sirt6 是否也 通过抑制 AD 中的 RGC 及其轴突损伤，发挥神经保护作用 线粒体功能障碍。未来，根据这项工作的试点数据，我们将进一步确定蜂窝 Sirt6 预防 AD 中 RGC 损伤和轴突变性的分子机制，以及 研究 Sirt6 的药物激活是否可以预防 AD 患者的视力丧失；此外，我们将测试是否增强 Sirt6 表达和活动可以减轻 AD 期间大脑的行为缺陷和神经退行性变 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 试点项目及其后续的未来研究将提供重要的新知识，可以指导 开发AD新疗法。