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: 9394901
• 负责人: Christiane D. Wrann
• 金额: $ 24.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9394901
• 关键词: Acute; Address; Affect; Aging; Alzheimer' s Disease; Animal Model; Animals; Area; Autistic Disorder; BDNF gene; Brain-Derived Neurotrophic Factor; Caring; Cell Culture Techniques; Cellular Metabolic Process; Cellular biology; Clinical Research; Cognition; Consult; Dana-Farber Cancer Institute; Data; Dendritic Spines; Department chair; Development; Development Plans; Diet; Disease; Disease Pathway; Doctor of Philosophy; Economics; Electrophysiology (science); Environment; Exercise; Faculty; Feedback; Fibronectins; Gene Expression; Genes; Genetic; Goals; Health; Hippocampus (Brain); Impaired cognition; Impairment; In Vitro; Individual; Injectable; Injection of therapeutic agent; Internal Ribosome Entry Site; Israel; Joints; Laboratory Research; Learning; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical Faculty; Medical center; Medicine; Memory; Mental disorders; Mentors; Mentorship; Modeling; Molecular; Morphology; 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; Transcription Coactivator; 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; exercise intervention; experience; experimental study; faculty mentor; 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; public health relevance; 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）：本研究提案概述了 Dana-Farber 癌症研究所和哈佛医学院的博士后研究员 Christiane D. Wrann 博士的五年职业发展计划，以在 Dana-Farber 癌症研究所和哈佛医学院细胞生物学和医学教授 Bruce Spiegelman 博士的指导下实现作为首席研究员的独立性。斯皮格曼博士是美国国家科学院院士，也是转录调控和外周运动有益影响方面的世界专家。重要的是，斯皮格曼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职。迈克尔·格林伯格博士将担任联合导师，并将为该项目提供神经生物学方面的专业知识。格林伯格博士是哈佛医学院神经生物学内森·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，BDNF 基因表达和突触可塑性领域的领导者，为我们对认知疾病（这些过程受到干扰）的理解做出了巨大贡献。 Greenberg 博士在指导博士后方面拥有超过 25 年的经验，并在指导博士后过渡到独立教职职位方面建立了成功的记录。此外，哈佛医学院医学教授兼神经科学项目教员 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 实验室和哈佛医学院周边校园的世界一流环境来实现提案中的目标。 该候选人在专注于疾病分子途径的创新研究方面拥有良好的记录。她曾在哈佛医学院附属的贝斯以色列女执事医疗中心和达纳法伯癌症研究所进行博士后培训，并在整个动物生理学和细胞水平的机制研究方面拥有丰富的经验。她的职业发展计划将尖端技术培训与职业发展活动结合起来，以促进她向独立过渡，包括正式课程作业、参加科学会议以及拥有其研究领域专业知识的联合导师委员会的支持。该计划使 Wrann 博士能够发展运动引起的突触可塑性和认知益处的分子机制方面的专业知识，并过渡到独立教职职位以建立自己的研究项目。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，其研究实验室致力于理解和逆转与衰老和神经退行性疾病相关的认知障碍。 认知障碍是由多种疾病引起的，例如衰老、阿尔茨海默病等神经退行性疾病，以及精神分裂症或自闭症等精神和神经发育障碍。与这种损伤相关的残疾是毁灭性的，照顾受影响个人的经济和社会成本是惊人的；然而，有效的治疗方案远远不够，这主要是由于缺乏治疗靶点。在各种啮齿动物模型和临床研究中，运动与改善认知功能有关，尤其是学习和记忆。然而，为了从运动干预中获得可药物靶标，需要更深入地了解调节运动引起的认知改善的分子机制。我的初步研究确定 FNDC5（包含 5 的纤连蛋白结构域 III）是一种有前途的新型调节剂，可以调节运动引起的认知益处（Wrann 等人，Cell Metabolism 2013）。基于这些数据，我假设 FNDC5 充当关键调节因子，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。该提案的目的是 通过整合细胞培养中的机制实验、遗传小鼠模型中的功能性电生理学和形态学研究以及行为测试，严格检验这一假设并评估 FNDC5 在认知中的作用。我将通过实现三个具体目标来实现这一目标。在目标 1 中，我将检验以下假设：运动诱导的 BDNF 表达需要 FNDC5，从而改善认知；在目标 2 中，我将检验 FNDC5 调节突触可塑性；在目标 3 中，我将检验 FNDC5 可以改善认知衰退小鼠模型中的认知功能。 这些实验的成功完成将有助于更好地理解运动影响突触可塑性和改善认知功能的分子机制。此外，它还为 FNDC5 如何改善认知衰退小鼠模型中的认知功能建立了一个框架，这可能代表了治疗这些疾病的一种新的治疗方法。