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介质

基本信息

批准号：
10366759
负责人：
Christiane D. Wrann
金额：
$ 47.36万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366759
关键词：
Address Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos 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 (Brain)Hormones Human Impaired cognition Impairment Injections Knock-out Knockout Mice Knowledge Learning Length Link Mediating Mediator of activation protein 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 base behavior test cognitive benefits cognitive change cognitive enhancement cognitive function dentate gyrus effective therapy endurance exercise experimental study human subject improved in vivo innovation insight loss of function middle age mouse model neurogenesis newborn neuron novel pre-clinical programs public health relevance success therapeutic candidate transcriptome

项目摘要

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.

项目摘要/摘要由衰老或神经退行性疾病引起的神经系统障碍，例如阿尔茨海默氏病（AD）尽管最有效的方法是发展有效的，但仍有重大的健康负担有趣的是，人类受试者和动物模型的研究很大程度上没有成功。这种体育锻炼，尤其是忍受运动，可以改善认知功能，主要是学习和记忆，通过增强海马中的成年神经发生的部分。分泌因素在锻炼中的细胞到细胞和跨器官谈话中的重要性。调解运动抑制非常有吸引力的药物靶标的认知益处。我们先前发表的数据确定了新颖的运动激素虹膜蛋白，从 FNDC5（含有5个纤连蛋白域III），作为促成认知益处的主要候选人根据原始数据，我们假设FNDC5通过其分泌形式irisin，起作用尽可能尽可能高认知功能的改善是通过整合机械的严格检验该假设分子技术，功能和形态研究以及遗传小鼠模型中的行为测试。我们将通过解决以下三个特定目标来实现这一目标：在AIM 1中，我们将确定是否是否肌肉衍生的虹膜颗粒是锻炼诱导的认知功能所必需的。虹膜蛋白是介导AIM 3的有益作用的活跃形式。虹膜蛋白的周围升高足以改善衰老的鼠标的认知功能。成功完成这些实验将更好地理解分子机制这会影响成年海马神经发生并改善认知功能项目将建立一个利用临床染色弹性弹性降低或AD的弹性弹性下降的框架。