Molecular mechanisms of exercise benefits in synapse plasticity and cognition

描述(由申请人提供)：本研究提案概述了克里斯蒂安·D·怀恩博士的五年职业发展计划，他是达纳-法伯癌症研究所和哈佛医学院的博士后研究员，在达纳-法伯癌症和哈佛医学院细胞生物学和医学教授布鲁斯·斯皮格曼博士的指导下，实现了作为首席研究员的独立。斯皮格尔曼博士是美国国家科学院院士，也是转录调控和外围运动的有益影响方面的世界专家。重要的是，斯皮格尔曼博士在指导科学家方面有着良好的记录，有20多名受训人员担任过学术教职。迈克尔·格林伯格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他的专业知识。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，在脑源性神经营养因子基因表达和突触可塑性领域处于领先地位，并为我们理解认知疾病做出了巨大贡献，在认知疾病中，这些过程受到干扰。格林伯格博士在指导博士后方面有超过25年的经验，并建立了指导博士后过渡到独立教师职位的成功记录。此外，哈佛医学院医学教授、神经科学项目教员布拉德福德·洛厄尔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参考。Wrann博士将利用Spiegelman实验室和哈佛医学院校园周围的世界级环境来实现提案中的目标。这位候选人在创新研究方面有很好的记录，重点是疾病的分子途径。她曾在贝丝以色列女执事医学中心和达纳-法伯癌症研究所(哈佛医学院的附属机构)进行博士后培训，并在整个动物生理学和细胞水平的机械研究方面都有经验。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，以促进她向独立的过渡，并包括正式的课程工作，参加科学会议，以及由在她的研究领域拥有专业知识的联合导师委员会提供支持。这项计划使莱恩博士能够在运动对突触可塑性和认知产生益处的分子机制方面积累专业知识，并过渡到独立的教职员工岗位，建立自己的研究项目。这位候选人的长期目标是成为一名独立的学术研究员和教师导师，拥有一个研究实验室，为理解和扭转与衰老和神经退行性疾病相关的认知障碍做出贡献。认知障碍是由各种情况引起的，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。与这种损害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令人震惊；然而，主要由于缺乏治疗目标，有效的治疗选择严重不足。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，为了从运动干预中获得可用药的靶点，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。我的初步研究确定FNDC5(纤维连接蛋白结构域III包含5)是一种有前途的、新的运动诱导认知益处的调节因子(Wrann等人，细胞代谢2013)。基于这些数据，我假设FNDC5起着关键的调节作用，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研究以及行为测试，严格测试这一假说并评估FNDC5在认知中的作用。我将通过解决三个具体目标来实现这一目标。在目标1中，我将验证FNDC5是运动诱导的BDNF表达所必需的假说，从而改善认知；在目标2中，FNDC5调节突触可塑性；在目标3中，FNDC5可以改善认知衰退小鼠的认知功能。这些实验的成功完成将使人们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的认知功能建立了一个框架，这可能代表着治疗这些疾病的一种新的治疗方法。

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.