Molecular mechanisms of exercise benefits in synapse plasticity and cognition

描述（由申请人提供）：本研究计划概述了丹娜-法伯癌症研究所和哈佛医学院博士后Christiane D. Wrann博士，D.V.M, Ph.D.博士，在丹娜-法伯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，作为一名独立的首席研究员，实现五年的职业发展计划。Spiegelman博士是美国国家科学院（National Academy of Sciences）的成员，也是转录调控和外周运动有益影响方面的世界级专家。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职。Michael Greenberg博士将作为共同导师，为项目的神经生物学方面提供专业知识。格林伯格博士是内森·马什·普西神经生物学教授，也是哈佛医学院神经生物学系主任。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军人物，为我们理解这些过程受到干扰的认知疾病做出了巨大贡献。格林伯格博士在指导博士后方面拥有超过25年的经验，并在指导博士后转变为独立教师职位方面取得了成功的记录。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实验室和哈佛医学院校园周围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良好的记录，重点是疾病的分子途径。她曾在Beth Israel Deaconess医疗中心和Dana- Farber癌症研究所（哈佛医学院附属机构）进行博士后培训，并在全动物生理学和细胞水平的机制研究方面都有经验。她的职业发展计划将尖端技术的培训与职业发展活动相结合，以促进她向独立过渡，包括正式的课程学习，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的运动诱导益处的分子机制方面发展专业知识，并过渡到独立的教师职位，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，在研究实验室为理解和逆转与衰老和神经退行性疾病相关的认知障碍做出贡献。认知障碍是由多种情况引起的，如衰老，神经退行性疾病，如阿尔茨海默病，精神和神经发育障碍，如精神分裂症或自闭症。与这种损害有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，有效的治疗方案严重不足，主要原因是缺乏治疗靶点。在各种啮齿动物模型和临床研究中，锻炼与认知功能的改善有关，尤其是学习和记忆。然而，为了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。我的初步研究发现FNDC5（含5的纤维连接蛋白结构域III）是一种有前景的新型运动诱导认知益处调节剂（Wrann et al., Cell Metabolism 2013）。基于这些数据，我假设FNDC5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

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.