Age-dependent SKN-1/NRF cytoprotection at the cost of metabolic homeostasis

年龄依赖性 SKN-1/NRF 细胞保护以代谢稳态为代价

基本信息

批准号：
10288687
负责人：
Sean P CURRAN
金额：
$ 36.22万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288687
关键词：
3xTg-AD mouse Address Administrative Supplement Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Animals Caenorhabditis elegans Cells Clinic Complex Cytoprotection Data Development Diet Disease Disease Marker Eating Food Funding Future Generations Genes Genetic Genetic Transcription Health Homeostasis Human Individual Invertebrates Light Link Longevity Macronutrients Nutrition Mammals Mediating Mediator of activation protein Metabolic Metabolic stress Modeling Molecular Mus Nerve Degeneration Neurons Nutraceutical Nutritional Study Onset of illness Organism Pathologic Pathway interactions Phenotype Physiology Publishing Research Scientist Severities Societies Stress System Testing Time Translating United States Work age related base chronic infection combat cost cost estimate genetic variant innovation large datasets model development mouse model next generation novel novel strategies novel therapeutic intervention pathogen pathogen exposure pathogenic bacteria pathogenic fungus pathogenic virus phrases programs response transcription factor

项目摘要

ABSTRACT OF SUPPLEMENT New approaches are needed to combat Alzheimer’s disease (AD), a neurodegeneration condition that affects millions of people in the United States at an estimated cost exceeding hundreds of billions of dollars. Despite decades of work a treatment does not exist. As such, the need for new models to accelerate our understanding of this debilitating disease are needed – but development of these models takes time. We propose using the well-established C. elegans model of AD to interrogate new models of AD pathology. Previously, our lab discovered a critical link for the cytoprotective transcription factors SKN-1 (in worms) and NRF2 (in mammals) for maintaining metabolic homeostasis in a diet-dependent manner. Moreover, we recently published that SKN-1 mediates one of the earliest responses to pathogen exposure. The “pathogen hypothesis” is an understudied idea that chronic infection by viral, bacterial, and/or fungal pathogens can be a potent contributor for sporadic AD onset during aging. In light of the high degree of conservation of SKN-1/NRF stress pathway responses in worms, mice, and humans that we have documented, we hypothesize that: (1) SKN-1/NRF2 is the central mediator of the “pathogen hypothesis” models of Alzheimer’s Disease; and (2) Diet-gene pairs influence AD pathology progression and severity. We focus by on our established gene and diet combinations in the context of well-established AD models as well as new paradigms that integrate pathogen exposure and responses on AD pathology. This project will engage a team of scientists to test novel and easily testable models of the pathogen hypothesis in C. elegans (Aim 1) and the impact of diet on AD markers (Aim 2). Together, this supplement will address the significance of two environmental conditions (pathogen exposure and diet) on established and novel AD models in C. elegans. Capitalizing on the facile genetic and molecular approaches, a sort generation time, and ease of culturing, C. elegans is the ideal model for this one-year administrative supplement project to rapidly acquire large data sets and integrate these findings into new studies of AD pathology in mammals. The results of these efforts will lead to new therapeutic approaches to treat AD.

补充摘要需要新的方法来对抗阿尔茨海默病（AD），这是一种影响神经退行性疾病的疾病美国数百万人的损失估计超过数千亿美元。几十年的工作并不存在一种治疗方法，因此需要新的模型来加速我们的治疗。需要了解这种使人衰弱的疾病，但这些模型的开发需要时间。建议使用完善的 AD 秀丽隐杆线虫模型来研究新的 AD 模型此前，我们的实验室发现了细胞保护性转录因子 SKN-1（在线虫）和 NRF2（哺乳动物）以依赖饮食的方式维持代谢稳态。此外，我们最近发表了 SKN-1 介导对病原体暴露的最早反应之一。 “病原体假说”是一个未经充分研究的观点，认为病毒、细菌和/或真菌的慢性感染鉴于衰老过程中的高程度，病原体可能是导致散发性 AD 发作的一个重要因素。在线虫、小鼠和人类中 SKN-1/NRF 应激途径反应的保守性根据文献记载，我们认为：(1) SKN-1/NRF2 是“病原体假说”的核心调节因素阿尔茨海默病模型；（2）饮食基因对影响 AD 病理进展和严重程度。重点关注我们在完善的 AD 模型背景下建立的基因和饮食组合作为整合病原体暴露和 AD 病理学反应的新范式，该项目将参与其中。一组科学家测试秀丽隐杆线虫病原体假说的新颖且易于测试的模型（目标 1）以及饮食对 AD 标志物的影响（目标 2）。两种环境条件（病原体暴露和饮食）对 C 中已建立的和新型 AD 模型的影响。利用简单的遗传和分子方法、一代代时间和简便性。培养，线虫是这个为期一年的行政补充项目快速获得的理想模型大数据集并将这些发现整合到哺乳动物 AD 病理学的新研究中。这些努力将带来治疗 AD 的新治疗方法。