FNDC5/irisin as a molecular mediator of exercise benefits in cognitive function

联系PD/PI：Wrann，Christian D。 联系PD/PI：Wrann，Christian D。 项目摘要/摘要 由衰老或神经退行性疾病引起的神经损伤，如阿尔茨海默病(AD)是 这是一个主要的、不断增长的健康负担。尽管尽了最大努力，开发有效疗法的传统方法 在很大程度上都不成功。有趣的是，对人类受试者和动物模型的研究都表明 体育锻炼，特别是耐力锻炼，可以改善认知功能，主要是学习和 记忆，部分是通过增强成年海马区的神经发生。最近的研究强调了 运动中分泌因子在细胞间和跨器官谈话中的重要性。隐秘的因素 调节运动对认知的益处代表着非常有吸引力的药物靶点。 我们之前发表的数据证实了一种新的运动荷尔蒙蝴蝶素，它被分解和分泌。 FNDC5(纤维连接蛋白结构域III包含5)，作为有助于认知益处的主要候选基因 锻炼身体。根据这一初步数据，我们推测FNDC5通过其分泌形式的虹膜蛋白， 作为一种关键的调节因子，将运动与成年海马神经发生联系起来，导致 认知功能的改善。我们的目标是通过整合机械论来严格检验这一假说 分子技术，功能和形态研究，以及遗传小鼠模型的行为测试。 我们将通过解决以下三个具体目标来实现这一目标：在目标1中，我们将确定是否 运动诱导的认知功能改善需要肌源性虹膜蛋白。在目标2中，我们将测试 淫羊藿素是调节运动有益效果的活性形式。在目标3中，我们将阐明 虹膜蛋白的外周升高足以改善衰老小鼠模型的认知功能。 成功地完成这些实验将有助于更好地理解分子机制。 因此，运动影响成人海马区的神经发生并改善认知功能。此外，这一点 该项目将建立一个框架，潜在地使用淫羊藿素来治疗衰老或AD的认知能力下降。 项目摘要/摘要第6页 项目摘要/摘要第6页

Contact PD/PI: Wrann, Christiane D. Contact PD/PI: Wrann, Christiane D. PROJECT SUMMARY/ABSTRACT Neurological impairment caused by aging or neurodegenerative diseases, such as Alzheimer's disease (AD) is a major and growing health burden. Despite best efforts, traditional approaches to develop effective therapies have been largely unsuccessful. Interestingly, studies in both human subjects and animal models have shown that physical activity, especially endurance exercise, can improve cognitive function, mainly learning and memory, in part by enhancing adult neurogenesis in the hippocampus. Recent studies have highlighted the importance of secreted factors in cell-to-cell and cross-organ talks in exercise. The secreted factors that mediate the cognitive benefits of exercise represent very attractive drug targets. Our previously published data identified the novel exercise hormone irisin, the cleaved and secreted from of FNDC5 (fibronectin-domain III containing 5), as a prime candidate contributing to the cognitive benefits of exercise. Based on this preliminary data, we hypothesize is that FNDC5, through its secreted form irisin, acts as a critical regulator linking exercise to adult hippocampal neurogenesis resulting in improvements in cognitive function. Our goal is to rigorously test this hypothesis by integrating mechanistic molecular techniques, functional and morphological studies, and behavioral testing in genetic mouse models. We will achieve this goal by addressing the following three Specific Aims: In Aim 1, we will determine whether muscle-derived irisin is required for exercise-induced improvement in cognitive function. In Aim 2, we will test if irisin is the active form to mediate the beneficial effects of exercise. In Aim 3, we will elucidate whether peripheral elevation of irisin is sufficient to improve cognitive function in aging mouse models. Successfully completing these experiments will provide a better understanding of the molecular mechanism whereby exercise affects adult hippocampal neurogenesis and improves cognitive function. In addition, this project will establish a framework for potentially using irisin to treat cognitive decline in aging or AD. Project Summary/Abstract Page 6 Project Summary/Abstract Page 6