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.

阿尔茨海默病 (AD) 约占痴呆症病例总数的三分之二，AD 病例数预计到 2050 年将增加两倍。确定调节 AD 的新途径不仅会改善我们的了解神经退行性疾病背后的机制，同时也将显着改善生活质量最近的人类研究揭示了 omega-3 水平与 omega-6 膳食脂质和大脑衰老然而，这种影响背后的具体途径仍然存在。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 (PUFA) 代谢产生 omega-3 和 omega-6 PUFA。通过花生四烯酸 (AA) 级联产生数百种称为氧脂质的脂质信号分子。在炎症、血压调节、血管生成和纤维化及其体内发挥稳态作用此外，最近的研究表明，特定的水平受到疾病进展的显着影响。氧脂质可能在 AD 中发挥重要作用 Aβ 和 tau 蛋白的沉积是 AD 的标志，并且衰老仍然存在。 AD 的关键风险因素之一因此，在本提案中，我们追求 Aβ 和 tau 的沉积。衰老会调节体内氧脂质水平，从而影响动物的神经健康。为了检验我们的假设，我们将通过汇集有机和有机领域的专业知识来开发一种多学科方法。分析化学家、神经生物学家、AD 研究人员和模型生物的使用我们将 1) 建立。 CYP450 PUFA 代谢物内源水平与 Aβ-、tau- 和衰老影响之间的关系诱导的神经变性；2) 确定特定氧脂质对 Aβ-、tau- 和衰老诱导的影响我们将使用秀丽隐杆线虫（C. elegans）作为模型生物来研究其影响。 Aβ 和 tau 蛋白以及衰老对 PUFA 代谢的影响，因为容易产生大量与年龄同步的蛋白人口，以及可用于开展这项研究的已建立的遗传工具的数量。衰老和神经退行性途径以及氧磷脂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高效液相色谱与串联质谱联用来确定秀丽隐杆线虫在生物体整个生命周期和转基因菌株中的氧脂质水平我们将测试受 Aβ 和 tau 沉积显着影响的 oxylipins 的效果。使用过度表达 Aβ 和 tau 的转基因菌株进行神经退行性分析中的 tau 和衰老。通过这个项目，我们可以找到一条对衰老和神经退行性疾病研究很重要的新途径。还可以解释 omega-3 和 omega-6 PUFA 对衰老的影响。