SIRTUIN1-mediated inhibition of p66shc lysine acetylation as a novel treatment for diabetic vasculopathy

 描述（由申请人提供）： 糖尿病是一个全球性的公共卫生问题。与普通人群相比，退伍军人受到糖尿病的影响。糖尿病给退伍军人带来了沉重的负担，使他们的死亡风险增加了一倍。大多数糖尿病退伍军人的住院和死亡 是由于血管并发症，如心肌梗塞和中风。糖尿病导致这些并发症，因为它促进血管内皮功能障碍并加速动脉粥样硬化。 氧化应激对血管功能具有许多有害作用，并且是糖尿病血管系统的显著特征。P66shc是一种在糖尿病血管中表达的蛋白质，它刺激氧化应激。P66shc是糖尿病血管功能障碍和加速动脉粥样硬化的主要因素。p66shc在糖尿病血管中是如何调节的尚不清楚。本申请的直接目标是了解糖尿病血管中p66shc功能的基本机制，最终目标是利用这些知识来预防和治疗糖尿病血管疾病。 本申请将探索糖尿病血管内皮中p66 shc和SIRTUIN 1（SIRT 1）赖氨酸脱乙酰酶之间的新关系。它的中心是新的假设，即糖尿病中内皮细胞p66 shc被赖氨酸乙酰化，赖氨酸乙酰化激活p66 shc， 赖氨酸乙酰化的p66shc在导致糖尿病血管功能障碍和加速动脉粥样硬化中起着不可或缺的作用，SIRT 1通过直接脱乙酰化内皮p66shc来改善糖尿病血管疾病。本申请中提出的研究将询问1）糖尿病引起的赖氨酸乙酰化如何在分子水平上激活p66shc，从而促进血管内皮中的氧化应激，以及2）如果p66shc不能被乙酰化，是否可以预防或延缓糖尿病血管功能障碍和疾病。它将通过使用独特的分子工具来解决这些问题，包括缺乏内皮SIRT1的小鼠和内皮p66shc不可乙酰化的小鼠。 为什么要研究SIRT1和p66shc之间的这种新关系？目前治疗或预防糖尿病血管疾病及其并发症（包括心脏病发作和中风）的疗法严重不足。即使降低血糖也被证明在预防糖尿病患者的动脉粥样硬化并发症方面基本无效。除此之外，还有几种药物已被开发为SIRT1的激活剂，并且在给予人类时是安全的。如果本申请中的研究证明SIRT1通过脱乙酰化p66shc在预防糖尿病的血管功能障碍和加速动脉粥样硬化中起主要有益作用，则这些SIRT1激活剂可以在治疗糖尿病血管疾病中找到新的用途。此外，表明p66shc的赖氨酸乙酰化是糖尿病血管疾病的主要机制，可以为开发靶向这种乙酰化途径的药物作为糖尿病血管并发症的新疗法打开大门。

 DESCRIPTION (provided by applicant): Diabetes is a worldwide public health problem. Veterans are disproportionally impacted by diabetes compared to the general population. Diabetes exacts a heavy toll on veterans, doubling their risk of death. The majority of hospitalizations and deaths in veterans with diabetes are due to vascular complications such as myocardial infarctions and strokes. Diabetes leads to these complications because it promotes dysfunction of the vascular endothelium and accelerates atherosclerosis. Oxidative stress has many deleterious effects on blood vessel function and is a prominent feature of the diabetic vasculature. P66shc is a protein expressed in diabetic blood vessels where it stimulates oxidative stress. P66shc is a major factor responsible for diabetic vascular dysfunction and accelerated atherosclerosis. How p66shc is regulated in diabetic blood vessels is not known. The immediate goal of this application is to understand the fundamental mechanism governing p66shc function in diabetic blood vessels, with the eventual goal of leveraging this knowledge to prevent and treat diabetic vascular disease. This application will explore a novel relationship between p66shc and the SIRTUIN1 (SIRT1) lysine deacetylase in the diabetic vascular endothelium. It centers on the novel hypothesis that endothelial p66shc is lysine acetylated in diabetes, that lysine acetylation activates p66shc, that lysine acetylated p66shc plays an indispensable role in leading to diabetic vascular dysfunction and accelerated atherosclerosis, and SIRT1 ameliorates diabetic vascular disease by directly deacetylating endothelial p66shc. Studies proposed in this application will ask 1) how lysine acetylation by diabetes activates p66shc at the molecular level, thus promoting oxidative stress in the vascular endothelium, and 2) whether diabetic vascular dysfunction and disease can be prevented or retarded if p66shc cannot be acetylated. It will address these points by using unique molecular tools including mice lacking endothelial SIRT1 and mice in which endothelial p66shc is not acetylatable. Why investigate this novel relationship between SIRT1 and p66shc? Current therapies to treat or prevent diabetic vascular disease and its attendant complications, including heart attacks and strokes, are woefully inadequate. Even reducing blood sugar has proven largely ineffective in preventing atherosclerotic complications of diabetics. Add to this that there are several pharmaceuticals that have been developed as activators of SIRT1 and are safe when given to humans. If studies in this application prove that SIRT1 plays a major beneficial role in preventing vascular dysfunction and accelerated atherosclerosis of diabetes by deacetylating p66shc, these SIRT1 activators could find a new use in the treatment of diabetic vascular disease. In addition, showing that lysine acetylation of p66shc is the principal mechanism responsible for diabetic vascular disease could open the door for developing pharmaceuticals that target this acetylation pathway as novel therapies for diabetic vascular complications.