Oxylipins, aging and Alzheimer’s disease

氧脂质、衰老和阿尔茨海默病

基本信息

批准号：
10642679
负责人：
Kin Sing Stephen Lee
金额：
$ 15.26万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642679
关键词：
Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Animals Arachidonic Acids Biological Biological Assay Biological Models Caenorhabditis elegans Cell Respiration Chemicals Coupled Cytochrome P450 Data Dementia Diet Dietary Fats Disease Progression Enzymes Epoxide hydrolase Fibrosis Future Genetic Goals Health Homologous Gene Human Inflammation Investigation Life Style Lipids Liquid Chromatography Longevity Measures Mediator Medical Metabolic Metabolism Methods Modeling Mus Nerve Degeneration Neurons Omega-3 Fatty Acids Omega-6 Fatty Acids Organism Pathogenesis Pathologic Pathway interactions Performance Phenotype Physical Fitness Physiology Play Polyunsaturated Fatty Acids Population Prostaglandin-Endoperoxide Synthase Prostaglandins Quality of life Research Research Personnel Role Sampling Signaling Molecule Testing Toxic Environmental Substances Transgenic Organisms Work abeta deposition aging brain aging population analytical method analytical tool angiogenesis bioinformatics pipeline blood pressure regulation design dietary effective therapy fatty acid metabolism hydroxy fatty acid improved in vivo interdisciplinary approach lipid mediator lipid metabolism model organism neurodegenerative phenotype novel overexpression success tandem mass spectrometry tau Proteins tool

项目摘要

Alzheimer’s disease (AD) comprises about two-thirds of the total dementia cases, and the number of AD cases is expected to triple by 2050. Identifying a new pathway that modulates AD will not only improve our understanding of the mechanism behind neurodegeneration, but will also significantly improve the quality of life of the aged population. Recent human studies revealed a causal relationship between the levels of omega-3 and omega-6 dietary lipids and aging of the brain. However, the specific pathway(s) behind such effects remains largely unknown. The overall goal of this proposal is to elucidate the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) metabolites in AD. Metabolism of omega-3 and omega-6 PUFAs generates hundreds of lipid-signaling molecules called oxylipins through the arachidonic acid (AA) cascade. These oxylipins play a homeostatic role in inflammation, blood pressure regulation, angiogenesis, and fibrosis, and their in vivo levels are significantly affected by disease progression. Furthermore, recent studies suggested that specific oxylipins may play an important role in AD. The deposition of Aβ and tau are hallmarks of AD, and aging remains one of the key risk factors of AD. Therefore, in this proposal, we hypothesize that deposition of Aβ and tau and aging modulate the in vivo oxylipin levels, which affects the neuronal health of animals. To test our hypothesis, we will develop a multidisciplinary approach by assembling expertise from organic and analytical chemists, neurobiologists, AD researchers and the use of a model organism. We will 1) establish the relationship between endogenous levels of CYP450 PUFA metabolites and the effect of Aβ-, tau-and aging- induced neurodegeneration and; 2) determine the effect(s) of specific oxylipins on Aβ-, tau-and aging induced neurodegeneration. We will use Caenorhabditis elegans (C. elegans) as a model organism to study the effect of Aβ and tau, and aging on PUFA metabolism because of the ease of generating large age-synchronized populations, and the number of established genetic tools available to carry out this research. Furthermore, many aging and neurodegenerative pathways and oxylipin pathways are conserved between C. elegans and humans. We will use state-of-the-art ultra-performance liquid chromatography coupled with tandem mass spectrometry to determine oxylipins levels in C. elegans over the lifespan of the organism and in transgenic strains that overexpress Aβ and tau. We will test the effect of oxylipins that are significantly affected by deposition of Aβ and tau and aging in neurodegenerative assays using transgenic strains that overexpress Aβ and tau. Upon success of this project, we could identify a new pathway important for aging and neurodegeneration research. Our results could also explain the effect(s) of omega-3 and omega-6 PUFAs on aging.

阿尔茨海默氏病（AD）约占总痴呆症病例的三分之二，AD病例的数量预计到2050 了解神经退行性背后的机制，但也将显着提高生活质量年龄人口。最近的人类研究揭示了omega-3和 omega-6饮食脂质和大脑衰老。但是，这种效果背后的特定途径仍然存在在很大程度上未知。该提案的总体目标是阐明omega-3和Omega-6的作用 AD中的多不饱和脂肪酸（PUFAS）代谢产物。 Omega-3和Omega-6 Pufas的代谢产生数百种脂质信号分子通过花生四烯酸（AA）级联反应称为黄磷脂。这些阿昔霉素在炎症，血压调节，血管生成和纤维化中发挥体内稳态作用，其体内疾病进展显着影响水平。此外，最近的研究表明黄吡啶可能在AD中起重要作用。 Aβ和TAU的沉积是AD的标志，并且衰老仍然存在 AD的关键风险因素之一。因此，在此提案中，我们假设Aβ和Tau的沉积以及衰老调节体内奥甲胺素水平，从而影响动物的神经元健康。为了检验我们的假设，我们将通过组装有机和分析化学家，神经生物学家，AD研究人员以及模型生物体的使用。我们将1）建立 CYP450 PUFA代谢物的内源水平与Aβ-，TAU和衰老的影响之间的关系诱导神经变性和； 2）确定特异性阿氧蛋白对Aβ-，tau和衰老诱导的影响神经变性。我们将使用秀丽隐杆线虫（秀丽隐杆线虫）作为模型生物来研究 Aβ和tau，以及PUFA代谢的老化，因为很容易产生大型同步人群以及可用于进行这项研究的已建立遗传工具的数量。此外，许多衰老途径和奥昔霉素途径在秀丽隐杆线虫和人类之间是保守的。我们将使用最先进的超表现液相色谱法，并串联质谱法至确定秀丽隐杆线虫在生物体的寿命和转基因菌株中的氧基蛋白水平过表达Aβ和tau。我们将测试阿氧蛋白的作用，这些作用受Aβ沉积显着影响使用过表达Aβ和TAU的转基因菌株的神经退行性测定中的tau和衰老。成功在该项目中，我们可以确定一种对衰老和神经退行性研究重要的新途径。我们的结果还可以解释Omega-3和Omega-6 Pufas对衰老的影响。