Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes

本行政副刊是对NOT-AG-20-034号公报的回应，题为《聚焦阿尔茨海默病的行政管理》 美国国立卫生研究院不专注于阿尔茨海默氏症的补助金补充。本补充文件的总体目标是 是利用我们现有的奖项，专注于糖尿病相关的生物钟紊乱如何做出贡献 以糖尿病对心脏的不良影响为平台，评估这些因素对心脏的影响 阿尔茨海默病(AD)及其相关痴呆(ADRD)。父应用程序测试假设 O-连接N-乙酰氨基葡萄糖(O-GlcNAc)修饰蛋白质在糖尿病损伤过程中的变化 心功能不全中自噬/有丝分裂吞噬的昼夜节律。有趣的是，昼夜节律失调， 糖尿病、蛋白质O-GlcN酰化紊乱、线粒体功能障碍和自噬/有丝分裂 也都与AD有关。目前尚不清楚1)O-GlcN酰化、有丝分裂和线粒体 大脑的功能受到昼夜节律的调节并受到糖尿病的影响；以及2)昼夜节律、O-GlcNAc和 有丝分裂操作改变了认知和神经病理。因此，我们目前的增刊申请将 验证与AD和ADRD相关的神经学和病理表型是 昼夜节律性Clock-O-GlcN酰化轴失调导致的后果 T2 DM加重的神经元有丝分裂和生物能量学。相同的小鼠基因和 药理操作、平行组织学和生化方法将用于大脑 在补充项目中，如父项目中所述。我们将与 以下两个目标：1)确定O-GlcN酰化、有丝分裂和 糖尿病会影响大脑中的线粒体功能，以及认知和神经病理； 确定是否存在吞丝分裂的遗传扰动、吞丝分裂的药理增强以及 生物钟的药理扰动影响O-GlcN酰化、有丝分裂、线粒体功能、 认知和神经病理学。其目标是对生物钟紊乱的各个方面获得新的基本见解。 以及糖尿病在AD发病机制中的作用，这些都是以前没有研究过的。获得了新的见解 这项研究将有助于确定缓解认知和神经病理缺陷的创新方法 广告。

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.