Dietary omega-3 (n-3) and omega-6 (n-6) fatty acids as novels activators of the anti-oxidant response

我们建议利用现有的专业知识和我们已经创建的模型系统，来确定饮食中的omega-3 （n-3）和omega-6 （n-6）脂肪酸是否激活nrf2依赖的抗氧化反应，从而防止神经退行性变。我们的重点是n-3和n-6脂肪酸，它们在人群队列研究中与降低神经变性风险有关。这种相关性背后的机制尚不清楚，但确定哪种脂肪酸会引起这种效果以及负责的机制对石油制造业具有战略价值。我们假设这种作用是由于n-3和n-6脂肪酸激活NRF2转录因子的能力，NRF2转录因子是细胞抗氧化反应途径的主要调节因子。我们的目标是确定1)饮食中的n-3和n-6脂肪酸是否激活NRF2反应，2)这种作用的机制，3)这种作用是否依赖于单一的n-3/n-6脂肪酸种类或复杂的饮食脂肪酸摄入，最后4)这种活性是否抑制神经退行性信号级联反应。为了实现这些目标，我们将结合体外筛选技术和体内动物饮食研究。这将允许评估NRF2在人类神经元中的激活，以及测量饮食中n-3和n-6脂肪酸摄入对神经退行性指标的影响。为了将这项工作与加拿大人口的饮食趋势联系起来，我们与两位农业行业代表合作。Soy20/20已经获得了加拿大人口中不同亚群体的石油消费模式的详细人口信息。这将使我们能够将我们的发现转化为实际的加拿大饮食消费模式，并确定那些脂肪酸谱与NRF2激活关系最密切的油。安大略省的粮食农民影响为特定目的（即工业应用与消费）种植的作物类型。与GFO合作将有助于将我们的研究结果转化为用于膳食消费的具体蒲式耳作物数量，既增加了市场份额，又为加拿大人提供了增值的饮食效益

We propose to leverage existing expertise and model systems we have created, to determine whether dietary omega-3 (n-3) and omega-6 (n-6) fatty acids activate the NRF2-dependent antioxidant response and as a result prevent neurodegeneration. Our focus is on the n-3 and n-6 fatty acids that have been associated with reduced risk of neurodegeneration in population cohort studies. The mechanism behind this correlation is unknown, yet determining which fatty acids elicit this effect and the mechanism responsible is of strategic value to the oil manufacturing industry. We hypothesize that this effect is due to the ability of n-3 and n-6 fatty acids to activate the NRF2 transcription factor, the master regulator of the cells anti-oxidant response pathway. Our goals are to determine 1) whether dietary n-3 and n-6 fatty acids activate the NRF2 response, 2) the mechanism underlying this effect, 3) whether the effect is dependent on single n-3/n-6 fatty acid species or complex dietary fatty acid intake and finally 4) whether this activity inhibits neurodegenerative-signaling cascades. To achieve these goals we will employ a combination of in vitro screening techniques as well as in vivo animal based dietary studies. This will allow for assessment of NRF2 activation in human neurons as well as measure the effect of dietary n-3 and n-6 fatty acid intake on neurodegenerative indices. To relate this work to the dietary trends within the Canadian population we have partnered with two agricultural industry representatives. Soy20/20 has acquired detailed population based information on oil consumption patterns amongst diverse sub groups of the Canadian population. This will allow us to translate our findings to actual Canadian dietary consumption patterns, and identify those oils whose fatty acid profiles correlate most highly with NRF2 activation. The Grain Farmers of Ontario influences the types of crops that are grown for specific purposes (ie industrial application verses consumption). Partnering with GFO will facilitate the translation of our findings into specific numbers of bushels of crops that are grown for dietary consumption, both increasing market share and providing value added dietary benefit to Canadians.**