Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes

本行政补充文件是对NOT-AG-20-034的回应，标题为“以阿尔茨海默氏症为重点的行政补充文件”。 补充美国国立卫生研究院的赠款金，而不是集中在阿尔茨海默氏病。本补充的总体目标 是利用我们现有的奖项，专注于糖尿病依赖的生物钟的破坏如何有助于 糖尿病对心脏的不良影响，作为评估这些因素对心脏的影响的平台。 阿尔茨海默病（AD）及其相关痴呆（ADRD）。父应用程序测试假设， 糖尿病损害期间O-连接的N-乙酰葡萄糖胺（O-GlcNAc）对蛋白质修饰的变化 心功能不全中自噬/线粒体自噬的昼夜节律调节有趣的是，昼夜节律失调， 糖尿病，蛋白质O-GlcNAc化的扰动，线粒体功能障碍和自噬/线粒体自噬， 也都与AD有关。目前尚不清楚1）O-GlcNAc化、线粒体自噬和线粒体 脑中的功能是昼夜节律调节的并且受糖尿病影响;以及2）昼夜节律、O-GlcNAc和 线粒体自噬操作改变认知和神经病理学。因此，我们目前的补充申请将 检验AD和ADRD相关的神经和病理表型是一种 昼夜节律钟-O-GlcNAc化轴失调的结果， 神经元线粒体自噬和生物能量学，其由T2 DM加重。同样的老鼠基因和 将在脑中使用药理学操作、平行组织学和生物化学方法 在补充项目中，如父项目中所述。我们将进行研究， 以下2个目的：1）确定O-GlcNAc酰化、线粒体自噬和 大脑中的线粒体功能以及认知和神经病理学受到糖尿病的影响;以及2） 确定线粒体自噬的遗传干扰，线粒体自噬的药理学增强， 生物钟的药理学扰动影响O-GlcNAc酰化、线粒体自噬、线粒体功能 认知和神经病理学。我们的目标是获得新的基本见解方面的昼夜节律中断 和糖尿病在AD发病机制中的作用，这在以前没有研究过。获得的新见解 这项研究将有助于确定创新的方法，以减轻认知和神经病理缺陷， AD.

This Administrative Supplement is in response to NOT-AG-20-034, entitled ‘Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease’. The overall goal of this supplement is to use our existing award, focused on how diabetes-dependent disruption of the circadian clock contributes to the adverse effects of diabetes on the heart, as the platform to assess the impact of these factors on Alzheimer’s disease (AD) and its related dementias (ADRD). The parent application tests the hypothesis that changes in the modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) during diabetes impairs circadian regulation of autophagy/mitophagy in cardiac dysfunction. Interestingly, circadian dysregulation, diabetes, perturbation of protein O-GlcNAcylation, mitochondrial dysfunction and autophagy/mitophagy have also all been linked to AD. It is currently unknown whether 1) O-GlcNAcylation, mitophagy, and mitochondrial function in the brain are circadian regulated and affected by diabetes; and 2) whether circadian, O-GlcNAc and mitophagy manipulations change cognition and neuropathology. Thus our current supplement application will test the hypothesis that AD and ADRD related neurological and pathological phenotypes are a consequence of dysregulation of the circadian clock-O-GlcNAcylation axis resulting in impaired neuronal mitophagy and bioenergetics that is exacerbated by T2DM. The same mouse genetic and pharmacological manipulations, parallel histology and biochemical methods will be used in the brain in the supplement project, as described in the parent project. We will perform studies with the following 2 aims: 1) Determine whether the circadian regulation of O-GlcNAcylation, mitophagy and mitochondrial function in the brain, as well as cognition and neuropathology, are affected by diabetes; and 2) Determine whether genetic perturbation of mitophagy, pharmacological enhancement of mitophagy, and pharmacological perturbation of circadian clock affect O-GlcNAcylation, mitophagy, mitochondrial function, cognition and neuropathology. The goal is to gain new fundamental insights into aspects of circadian disruption and diabetes in the pathogenesis of AD, which have not been investigated previously. New insights gained from this study will help identify innovative approaches for alleviating cognitive and neuropathological deficits in AD.