SIRT6 and Alzheimer Disease

这个补充项目的主要目标是调查是否获得的功能， 长寿基因sirtuin 6（SIRT 6）可预防阿尔茨海默病（AD）。老年痴呆症- 重点行政补充是一个合乎逻辑的扩展，并在我们的积极母公司的范围内 题为“SIRT 6和血管内皮稳态”的R 01资助。早期研究 证明SIRT 6参与端粒维持，DNA修复，基因组完整性， 能量代谢和炎症，最终调节寿命。我的实验室 先前产生的全局SIRT 6单倍不足和内皮特异性SIRT 6 基因敲除小鼠模型，并证明SIRT 6在维持血管内皮细胞的生长中起着关键作用。 内皮功能和限制动脉粥样硬化。通过在我们的父RO 1项目上工作， 最近创建了人源化SIRT 6转基因过表达小鼠模型，其中人 SIRT 6基因以条件诱导的方式在小鼠ROSA 26基因座中被遗传工程化 使用Cre/Loxp技术。我们的初步观察表明， 小鼠中的人SIRT 6保护免受内皮功能障碍、炎症和动脉粥样硬化。 重要的是，最近的研究结果还表明，SIRT 6在脑组织中的表达减少， AD小鼠模型和AD患者，提示SIRT 6也可能是一种新的潜在的 以治疗或预防AD。然而，SIRT 6在AD中的潜在保护作用 尚未成立。基于SIRT 6在DNA修复、抗炎 和抗衰老，我们假设SIRT 6的遗传和药理学激活可以保护 再次AD。在这个提议中，我们将充分利用我们新的人源化SIRT 6转基因小鼠模型， 探索SIRT 6过表达是否能防止AD的发展。此外，委员会认为， 新发现的SIRT 6激活剂将被用来测试药理学SIRT 6是否 激活加剧了AD病理。总的来说，本文提出的研究提供了一个 开始定义SIRT 6在拮抗淀粉样斑块形成中的潜在作用 在AD中。这些研究的结果应该有助于我们找到一种治疗方法或预防方法。 阿尔茨海默氏症和其他类型的痴呆症，并最终将我们的研究进展转化为 改善对老年痴呆症患者的护理。

The primary goal of this supplement project is to investigate whether the gain-of-function of the longevity gene sirtuin 6 (SIRT6) protects against Alzheimer disease (AD). This Alzheimer’s- focused administrative supplement is a logical expansion and within the scope of our active parent R01 grant entitled “SIRT6 and vascular endothelial homeostasis”. Early studies have demonstrated that SIRT6 is involved in telomere maintenance, DNA repair, genome integrity, energy metabolism, and inflammation, which ultimately regulate life span. My laboratory previously generated both global SIRT6 haploinsufficient and endothelium-specific SIRT6 knockout mouse models and demonstrated that SIRT6 plays a pivotal role in maintaining vascular endothelial function and limiting atherosclerosis. By working on our parent RO1 project we have recently created a humanized SIRT6 transgenic overexpression mouse model, in which human SIRT6 gene is genetically engineered in mouse ROSA26 locus in a conditionally inducible manner with the Cre/Loxp technology. Our nascent observations suggest that genetic overexpression of human SIRT6 in mice protects against endothelial dysfunction, inflammation, and atherosclerosis. Importantly, recent findings also reveal that SIRT6 expression in the brain tissues is decreased in AD mouse model and AD patients, suggesting that SIRT6 could also be a new potential therapeutic target to treat or prevent AD. However, the potential protective role of SIRT6 in AD has not been established. Based on the multifunction of SIRT6 in DNA repair, anti-inflammation and anti-aging, we hypothesized that genetic and pharmacological activation of SIRT6 protects again AD. In this proposal, we will fully utilize our novel humanized SIRT6 transgenic moue model to explore whether SIRT6 overexpression protects against the development of AD. Furthermore, the newly discovered SIRT6 activator will be exploited to test whether pharmacological SIRT6 activation alleviates AD pathologies. Collectively, the studies proposed herein provide a framework to begin defining a potential role of SIRT6 in antagonizing the amyloid plaque formation in AD. The findings resulting from these studies should help us find a treatment or way to prevent Alzheimer's and other types of dementia, and eventually translate our research advances into improved care for people with Alzheimer’s disease.