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

副刊摘要 需要新的方法来对抗阿尔茨海默病(AD)，这是一种影响 在美国有数百万人，估计成本超过数千亿美元。尽管 几十年的工作，一种治疗方法并不存在。因此，需要新的模式来加快我们的 需要了解这种使人衰弱的疾病，但开发这些模型需要时间。我们 建议使用成熟的AD线虫模型来审问AD的新模型 病理学。此前，我们的实验室发现了细胞保护性转录因子SKN-1(在 NRF2(在哺乳动物中)，以依赖饮食的方式维持代谢动态平衡。 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”是一个未被充分研究的观点，即病毒、细菌和/或真菌的慢性感染。 在衰老过程中，病原体可能是散发性AD发病的有力贡献者。鉴于……的高度 在蠕虫、小鼠和人类中SKN-1/NRF应激途径反应的保守性 ，我们假设：(1)SKN-1/NRF2是“病原体假说”的中心介体。 阿尔茨海默病的模型；(2)饮食-基因对影响AD的病理进展和严重程度。我们 通过在已建立的AD模型的背景下关注我们已建立的基因和饮食组合 作为整合病原体暴露和AD病理反应的新范式。该项目将与 一组科学家测试线虫病原体假说的新颖且易于测试的模型(目标1) 饮食对AD标志物的影响(目标2)。综上所述，本副刊将阐述 两种环境条件(病原体暴露和饮食)对已建立的和新的AD模型在C. 优雅女装。利用便捷的遗传和分子方法、某种代时和易用性 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式 大量数据集，并将这些发现整合到哺乳动物AD病理的新研究中。结果是 这些努力将导致治疗AD的新的治疗方法。

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.