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

证据摘要 需要新的方法来对抗阿尔茨海默病（AD），这是一种神经退行性疾病， 美国数百万人，估计成本超过数千亿美元。尽管 几十年的工作，一个治疗不存在。因此，需要新的模式来加速我们的 我们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C。elegans AD模型来研究AD的新模型 病理以前，我们的实验室发现了细胞保护性转录因子SKN-1的关键环节（在 蠕虫）和NRF 2（在哺乳动物中）用于以饮食依赖性方式维持代谢稳态。 此外，我们最近发表了SKN-1介导了对病原体暴露的最早反应之一。 “病原体假说”是一个未充分研究的观点，即病毒、细菌和/或真菌的慢性感染 病原体可能是衰老过程中散发性AD发作的有力因素。鉴于高度的 我们在蠕虫、小鼠和人类中保存了SKN-1/NRF应激途径反应， 我们推测：（1）SKN-1/NRF 2是“病原体假说”的中心介导因子。 饮食-基因对影响AD病理学进展和严重程度。我们 我们还将重点放在我们在完善的AD模型背景下建立的基因和饮食组合上 作为整合病原体暴露和AD病理学反应的新范例。该项目将参与 一个科学家小组测试了新的和容易测试的病原体假设模型，在C。elegans（Aim 1） 以及饮食对AD标志物的影响（目的2）。总之，本补编将讨论以下问题的重要性： 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. 优雅利用简单的遗传和分子方法，一个排序的世代时间，和容易的 培养、C. elegans是这个为期一年的行政补充项目的理想模式，以迅速获得 大型数据集，并将这些发现整合到哺乳动物AD病理学的新研究中。的结果 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.