FNDC5/irisin as a Molecular Mediator of Exercise Benefits in Cognitive Function

FNDC5/irisin 作为运动对认知功能有益的分子调节剂

• 批准号: 10747024
• 负责人: Christiane D. Wrann
• 金额: $ 1.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10747024
• 关键词: Acceleration; Address; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Brain; Cells; Clinical Research; Communication; Data; Development; Discrimination; Disease; Drug Targeting; Exercise; Fibronectins; Genetic; Genetic Models; Genetic Transcription; Goals; Health; Hippocampus; Hormones; Human; Impaired cognition; Impairment; Injections; Knock-out; Knockout Mice; Knowledge; Learning; Length; Link; Mediating; Mediator; Memory; Molecular; Morphology; Mus; Muscle; Muscle function; Neurodegenerative Disorders; Neurologic; Neurons; Organ; Peripheral; Physical activity; Proteins; Publishing; Rejuvenation; Running; Serum; Skeletal Muscle; Source; Stroke; Study models; Tail; Techniques; Testing; Therapeutic; Tissue Model; Transgenic Mice; Veins; Work; adult neurogenesis; behavior test; cognitive benefits; cognitive change; cognitive enhancement; cognitive function; dentate gyrus; effective therapy; endurance exercise; experimental study; human model; human subject; improved; in vivo; innovation; insight; loss of function; middle age; mouse model; neurogenesis; neuroprotection; newborn neuron; novel; pre-clinical; programs; public health relevance; success; therapeutic candidate; transcriptome

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.

项目概要/摘要 由衰老或神经退行性疾病（例如阿尔茨海默氏病 (AD)）引起的神经损伤 一个重大且日益严重的健康负担。尽管尽了最大努力，开发有效疗法的传统方法 基本上都没有成功。有趣的是，对人类受试者和动物模型的研究表明 身体活动，特别是耐力运动，可以改善认知功能，主要是学习和 记忆，部分是通过增强海马体中的成人神经发生来实现的。最近的研究强调 分泌因子在运动中细胞间和跨器官对话中的重要性。所分泌的因素 调节运动的认知益处是非常有吸引力的药物靶标。 我们之前发表的数据鉴定了新型运动激素鸢尾素，它是从 FNDC5（包含 5 的纤连蛋白结构域 III），作为有助于认知益处的主要候选者 锻炼。根据这些初步数据，我们假设 FNDC5 通过其分泌形式鸢尾素， 作为将运动与成人海马神经发生联系起来的关键调节器，导致 认知功能的改善。我们的目标是通过整合机制来严格检验这一假设 分子技术、功能和形态学研究以及遗传小鼠模型的行为测试。 我们将通过实现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 肌肉来源的鸢尾素是运动引起的认知功能改善所必需的。在目标 2 中，我们将测试是否 鸢尾素是调节运动有益效果的活性形式。在目标 3 中，我们将阐明是否 外周鸢尾素的升高足以改善衰老小鼠模型的认知功能。 成功完成这些实验将有助于更好地理解分子机制 运动会影响成人海马神经发生并改善认知功能。此外，这 该项目将建立一个框架，可能使用鸢尾素来治疗衰老或 AD 引起的认知能力下降。