Molecular mechanisms of exercise benefits in synapse plasticity and cognition

运动有益于突触可塑性和认知的分子机制

• 批准号: 8853349
• 负责人: Christiane D. Wrann
• 金额: $ 11.15万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853349
• 关键词: Acute; Address; Affect; Aging; Alzheimer' s Disease; Animal Model; Animals; Area; Autistic Disorder; Brain-Derived Neurotrophic Factor; Caring; Cell Culture Techniques; Cells; Cellular biology; Clinical Research; Cognition; Consult; Dana-Farber Cancer Institute; Data; Dendritic Spines; Development; Development Plans; Diet; Disease; Disease Pathway; Doctor of Philosophy; Economics; Environment; Exercise; Faculty; Feedback; Fibronectins; Gene Expression; Genes; Genetic; Goals; Health; Hippocampus (Brain); Impaired cognition; Impairment; In Vitro; Individual; Injection of therapeutic agent; Internal Ribosome Entry Site; Intervention; Israel; Joints; Laboratory Research; Learning; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical Faculty; Medical center; Medicine; Memory; Mental disorders; Mentors; Mentorship; Metabolism; Modeling; Molecular; Mus; Neurobiology; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neurons; Neurosciences; Obesity; Parkinson Disease; Performance; Physiology; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Process; Proxy; RNA Interference; Research; Research Personnel; Research Proposals; Rodent Model; Role; Schizophrenia; Scientist; Slice; Stroke; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic; Training; Transcriptional Regulation; Transgenic Mice; United States National Academy of Sciences; Work; base; behavior test; career development; cognitive function; cost; critical period; density; disability; effective therapy; experience; gain of function; improved; in vivo; innovation; loss of function; medical schools; meetings; member; morris water maze; mouse model; nestin protein; novel; novel therapeutic intervention; object recognition; post-doctoral training; postnatal; professor; programs; research study; social; therapeutic target

DESCRIPTION (provided by applicant): This research proposal outlines a five year career development plan for Dr. Christiane D. Wrann, D.V.M, Ph.D., postdoctoral research fellow at Dana-Farber Cancer Institute and Harvard Medical School, to achieve independence as a principal investigator under the mentorship of Bruce Spiegelman, Ph.D., Professor of Cell Biology and Medicine at the Dana-Farber Cancer and Harvard Medical School. Dr. Spiegelman is a member of the National Academy of Sciences and a world expert on transcriptional regulation and the beneficial effects of exercise in the periphery. Importantly, Dr. Spiegelman has a strong track record of mentoring scientists with over 20 trainees holding academic faculty positions. Dr. Michael Greenberg, PhD will function as co-mentor and will provide his expertise for the neurobiological aspects of the project. Dr. Greenberg is the Nathan Marsh Pusey Professor of Neurobiology and Chair of the Department of Neurobiology at Harvard Medical School. He is a member of the National Academy of Sciences, a leader in the field of BDNF gene expression and synapse plasticity, and has contributed greatly to our understanding of diseases of cognition, in which these processes are disturbed. Dr. Greenberg has more than 25 years of experience in mentoring postdocs and has established a successful record of guiding postdocs as they transition into independent faculty positions. In addition, Dr. Bradford Lowell, Professor of Medicine at Harvard Medical School and faculty member within the Program in Neuroscience, will provide his expertise in dissecting neurocircuits as a consult for Dr. Wrann's training in electrophysiological techniques. Dr. Wrann will take advantage of the world class environment at the Spiegelman lab and surrounding Harvard Medical School campus to achieve the aims in the proposal. The candidate has a strong track record of innovative research with a focus on the molecular pathways of diseases. She has performed postdoctoral training at the Beth Israel Deaconess Medical Center and the Dana- Farber Cancer Institute, affiliates of Harvard Medical School, and has experience in both, whole animal physiology and mechanistic studies at the cellular level. Her career development plan combines training in cutting-edge techniques with career development activities to facilitate her transition to independence and includes formal course work, attending scientific meetings, and support from a joint mentor committee with expertise in her area of research. This plan allows Dr. Wrann to develop expertise in the molecular mechanisms of exercise-induced benefits in synapse plasticity and cognition and to transition into independent faculty position to establish her own research program. The candidate's long-term goal is to become an independent academic investigator and faculty mentor with a research laboratory contributing towards understanding and reversing cognitive impairment associated with aging and neurodegenerative diseases. Cognitive impairment is caused by a variety of conditions such as aging, neurodegenerative diseases such as Alzheimer's disease, and psychiatric and neurodevelopmental disorders such as schizophrenia or autism. The disability associated with such impairment is devastating and the economic and social costs of caring for the affected individuals are staggering; yet effective treatment options are woefully inadequate, primarily due to a lack of therapeutic targets. Exercise has been linked to improved cognitive function, especially learning and memory, in various rodent models as well as in clinical studies. However, to derive druggable targets from exercise interventions a much deeper understanding of the molecular mechanisms that regulate exercise- induced improved cognition is required. My preliminary studies identify FNDC5 (fibronectin-domain III containing 5) as a promising and novel regulator of exercise-induced benefits on cognition (Wrann et al., Cell Metabolism 2013). Based on these data, I hypothesize that FNDC5 acts as a critical regulator that links exercise to BDNF expression and synapse plasticity, and thereby to improvements in cognitive function. The objective of this proposal is to rigorously test this hypothesis and evaluate the role of FNDC5 in cognition, by integrating mechanistic experiments in cell culture, functional electrophysiological and morphological studies in genetic mouse models, and behavioral testing. I will achieve this objective by addressing three Specific Aims. In Aim 1 I will test the hypothesis that FNDC5 is required for exercise-induced BDNF expression, which causes improved cognition, in Aim 2 that FNDC5 regulates synaptic plasticity, and in Aim 3 that FNDC5 can improve cognitive function in murine models of cognitive decline. Successful completion of these experiments will provide a better understanding of the molecular mechanism whereby exercise affects synaptic plasticity and improves cognitive function. In addition, it establishes a framework for how FNDC5 can improve cognitive function in murine models of cognitive decline, which may represent a novel therapeutic approach for treating these conditions.

描述（由申请人提供）： 本研究计划书概述了Christiane D博士的五年职业发展计划。Wrann，D.V.M，Ph.D.，丹娜-法伯癌症研究所和哈佛医学院的博士后研究员，在布鲁斯斯皮格曼博士的指导下作为主要研究者实现独立，丹娜-法伯癌症和哈佛医学院细胞生物学和医学教授。Spiegelman博士是美国国家科学院院士，也是转录调控和运动对外周有益影响的世界专家。重要的是，Spiegelman博士在指导科学家方面有着良好的记录，有20多名学员担任学术教师职位。Michael Greenberg博士将担任共同导师，并将为该项目的神经生物学方面提供专业知识。格林伯格博士是哈佛医学院神经生物学的内森·马什·普西教授和神经生物学系主任。他是美国国家科学院院士，是BDNF基因表达和突触可塑性领域的领导者，对我们理解认知疾病做出了巨大贡献，这些疾病中这些过程受到干扰。格林伯格有超过25年的指导博士后的经验，并建立了指导博士后，因为他们过渡到独立的教师职位的成功记录。此外，哈佛医学院医学教授、神经科学项目教员Bradford Lowell博士将提供他在解剖神经回路方面的专业知识，作为Wrann博士电生理技术培训的顾问。Wrann博士将利用Spiegelman实验室和周围哈佛医学院校园的世界级环境来实现提案中的目标。 候选人在创新研究方面有着良好的记录，重点是疾病的分子途径。她曾在贝丝以色列女执事医疗中心和哈佛医学院附属的达纳-法伯癌症研究所进行博士后培训，并在细胞水平的整体动物生理学和机制研究方面都有经验。她的职业发展计划将尖端技术培训与职业发展活动相结合，以促进她向独立过渡，并包括正式的课程工作，参加科学会议，以及在她的研究领域拥有专业知识的联合导师委员会的支持。该计划允许Wrann博士在突触可塑性和认知方面发展运动诱导益处的分子机制方面的专业知识，并过渡到独立的教师职位，以建立自己的研究计划。候选人的长期目标是成为一名独立的学术研究者和教师导师，拥有一个研究实验室，有助于理解和逆转与衰老和神经退行性疾病相关的认知障碍。 认知障碍是由多种病症引起的，例如衰老、神经退行性疾病（如阿尔茨海默病）以及精神和神经发育障碍（如精神分裂症或自闭症）。与这种损伤相关的残疾是毁灭性的，照顾受影响的个人的经济和社会成本是惊人的;然而，有效的治疗选择严重不足，主要是由于缺乏治疗目标。在各种啮齿动物模型和临床研究中，运动与改善认知功能，特别是学习和记忆有关。然而，要从运动干预中获得药物靶点，需要对调节运动诱导的认知改善的分子机制有更深入的了解。我的初步研究将FNDC 5（含有5的纤连蛋白结构域III）鉴定为运动诱导的对认知的益处的有希望的和新的调节剂（Wrann等人，Cell Metabolism 2013）。基于这些数据，我假设FNDC 5作为一个关键的调节器，将运动与BDNF表达和突触可塑性联系起来，从而改善认知功能。这项建议的目的是 通过整合细胞培养中的机制实验，遗传小鼠模型中的功能电生理和形态学研究以及行为测试，严格测试这一假设并评估FNDC 5在认知中的作用。我将通过三个具体目标来实现这一目标。在目标1中，我将测试FNDC 5是运动诱导的BDNF表达所需的假设，这导致认知的改善，在目标2中，FNDC 5调节突触可塑性，在目标3中，FNDC 5可以改善认知功能下降的小鼠模型中的认知功能。 这些实验的成功完成将提供一个更好地了解运动影响突触可塑性和改善认知功能的分子机制。此外，它还建立了FNDC 5如何改善认知衰退小鼠模型中的认知功能的框架，这可能代表了治疗这些疾病的新治疗方法。

项目成果

FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain.

• DOI: 10.3233/bpl-150019
• 发表时间: 2015
• 期刊: Brain plasticity (Amsterdam, Netherlands)
• 作者: Wrann CD

Neuroprotective potential of exercise preconditioning in stroke.

• 发表时间: 2017
• 期刊: Conditioning medicine
• 作者: M. R. Islam;Michael F. Young;C. Wrann