O-GLCNAC HOMEOSTASIS REGULATES MITOCHONDRIAL FUNCTION IN ALZHEIMER'S DISEASE

O-GLCNAC 稳态调节阿尔茨海默病的线粒体功能

基本信息

批准号：
10611377
负责人：
Chad Eric Slawson
金额：
$ 62.52万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611377
关键词：
Affect Aftercare Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker American Amino Acids Amyloid Antioxidants Categories Cell Cycle Cell Line Cell physiology Cells Chronic Citric Acid Cycle Clinical Pathways Cues Cytoplasmic Protein Data Development Diagnostic Disease Disease Progression Electron Transport Environment Enzymes Etiology Gene Expression Genes Genetic Transcription Glucosamine Homeostasis Hormones Impairment Inflammation Intervention Link Mass Spectrum Analysis Measures Metabolic Metabolic Diseases Metabolic dysfunction Methods Mitochondria Mitochondrial Proteins Modification Morphology Mus Nuclear Proteins Nutrient O-GlcNAc transferase Oxidative Stress Physiology Post-Translational Protein Processing Prevention Production Proteins Proteome Proteomics Public Health Publishing Reactive Oxygen Species Regulation Research Respiration Role Sampling Serine Signal Transduction Site Symptoms Testing Threonine Tissues Transcriptional Regulation Translations age related animal tissue biological adaptation to stress cell injury diagnostic biomarker environmental change extracellular inhibitor knock-down mitochondrial dysfunction mouse model neurofibrillary tangle formation neuronal metabolism novel novel therapeutics nuclear factor-erythroid 2 overexpression peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase protein expression response spatial memory tau Proteins transcription factor transcriptome

项目摘要

Currently, 5.4 million Americans are suffering from Alzheimer’s disease (AD), which is the only major disease lacking good prevention methods, treatments, or a cure. Recent evidence suggests that age related impairment of mitochondrial function and increased reactive oxygen species (ROS) production contribute to cellular damage and AD progression. The object of this proposal is to understand the affects of O-GlcNAcylation on mitochondrial function and the development of AD. O-GlcNAc is categorized by the addition of a single O-linked β-N-acetyl-D-glucosamine moiety to serine/threonine amino acids of nuclear and cytoplasmic proteins. This modification is responsive to extracellular signals such hormones, nutrients, and environmental cues and is involved in regulating numerous cellular functions such as the cell cycle, stress response, transcription, and translation. The enzymes responsible for processing the modification are O-GlcNAc transferase (OGT), which adds the modification, and O-GlcNAcase (OGA), which removes the modification. Importantly, changes in O-GlcNAcylation alter mitochondrial function. Cells actively maintain homeostatic levels in O-GlcNAc, and cells will alter the expression of OGT and OGA to modulate O-GlcNAcylation due to changes in the environment. We contend that O-GlcNAcylation is disrupted in chronic metabolic disease, which exacerbates the decline in mitochondrial function. We have demonstrated that over-expression of OGT or OGA causes large changes in protein expression of electron transport chain and Krebs cycle proteins, respiration is impaired, and mitochondrial morphology is disrupted. These data suggest that alterations to O-GlcNAc homeostasis would affect mitochondrial function exacerbating AD. In the current proposal, we will determine the mechanisms as to how O-GlcNAcylation regulates cellular function. First, we will identify changes to the transcriptome, proteome, and O-GlcNAcome in mouse models of AD or after loss of OGT. We will then determine how disrupted O-GlcNAc homeostasis affects electron transport chain function and metabolic gene expression. We will address the effect of OGA inhibitors on ameliorating mitochondrial dysfunction in AD mouse models. Furthermore, we will explore how O-GlcNAcylation influences mitochondrial anti-oxidant response. Our preliminary data shows that alterations in O-GlcNAc induce changes in anti-oxidant response and NRF2 activity, a critical transcription factor controlling the transcription of anti-oxidant genes. We will ascertain the mechanistic role of O-GlcNAc in regulating NRF2 transcriptional activity and protein interactions. Finally, we will use AD patient samples to identify the potential to use of O-GlcNAc, OGT or OGA as AD biomarkers. These studies will provide new mechanistic details into how O-GlcNAcylation affects mitochondrial function, how O-GlcNAc influences anti-oxidant response, NRF2 function, and will provide new pathways for clinical intervention of AD.

目前，有540万美国人患有阿尔茨海默氏病（AD），这是唯一的主要疾病缺乏良好的预防方法，治疗方法或治愈方法。最近的证据表明与年龄有关线粒体功能的损害和活性氧（ROS）产生增加有助于细胞损伤和AD进展。该建议的目的是了解O-Glcnacylation对线粒体功能和AD发展的影响。 O-GLCNAC通过加法进行分类单个O连接的β-N-乙酰基-D-葡萄糖部分，核和苏氨酸氨基酸的核和苏氨酸氨基酸细胞质蛋白。这种修饰对细胞外信号有反应环境线索，并参与调节许多细胞功能，例如细胞周期，应力响应，转录和翻译。负责处理该修饰的酶是O-GLCNAC转移酶（OGT），该酶添加了修饰和O-GlCNACase（OGA），它去除修改。重要的是，O-Glcnacylation的变化会改变线粒体功能。细胞积极维护 O-GLCNAC中的稳态水平，细胞将因环境变化而改变OGT和OGA的表达以调节O-Glcnacylation。我们认为O-Glcnacylation在慢性中被破坏代谢疾病，加剧了线粒体功能的下降。我们已经证明，OGT或OGA的过表达会导致电子传输链和KREB的蛋白质表达发生巨大变化循环蛋白，呼吸受损，线粒体形态受到破坏。这些数据表明 O-GLCNAC稳态的改变会影响线粒体功能加剧AD。在电流中提案，我们将确定O-Glcnacylation如何调节细胞功能的机制。首先，我们将确定AD鼠标模型中转录组，蛋白质组和O-GlCNACOME的变化或丢失后 OGT。然后，我们将确定O-GLCNAC稳态破坏如何影响电子传输链功能和代谢基因表达。我们将解决OGA抑制剂对改善线粒体的影响 AD鼠标模型中的功能障碍。此外，我们将探讨O-GlcNacylation如何影响线粒体抗氧化剂反应。我们的初步数据表明，O-GLCNAC的改变会诱导抗氧化剂的变化反应和NRF2活性，这是控制抗氧化基因转录的关键转录因子。我们将确定O-GLCNAC在调节NRF2转录活性和蛋白质中的机械作用互动。最后，我们将使用AD患者样品来确定使用O-GLCNAC，OGT或OGA的潜力作为广告生物标志物。这些研究将为O-Glcnacylation如何影响新的机械细节线粒体功能，O-GLCNAC如何影响抗氧化剂反应，NRF2功能，并将提供新的 AD临床干预的途径。