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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：该研究建议概述了D.V.M Christiane D. Wrann博士的五年职业发展计划Dana-Farber癌症和哈佛医学院的细胞生物学和医学教授Bruce Spiegelman博士的指导下的首席研究员。 Spiegelman博士是美国国家科学院的成员，是转录监管的世界专家和外围运动的有益影响。重要的是，Spiegelman博士在指导科学家方面拥有良好的记录，拥有20多名学员担任学术职位。迈克尔·格林伯格（Michael Greenberg）博士将担任联合学博士，并将为该项目的神经生物学方面提供他的专业知识。 Greenberg博士是Nathan Marsh Pusey神经生物学教授，哈佛医学院神经生物学系主任。他是美国国家科学院的成员，他是BDNF基因表达和突触可塑性领域的领导者，并为我们对认知疾病的理解做出了巨大贡献，其中这些过程受到干扰。格林伯格博士在指导博士后有25年以上的经验，并在过渡到独立教职员工职位时成功地指导了博士后。此外，哈佛医学院医学教授兼神经科学计划的教职员工布拉德福德·洛厄尔（Bradford Lowell）博士将提供他在神经电路上的专业知识，作为Wrann博士对电生理技术培训的咨询。 Wrann博士将在Spiegelman实验室和周围的哈佛医学院校园里利用世界一流的环境，以实现该提案的目标。候选人具有创新研究的良好记录，重点是疾病的分子途径。她曾在贝丝以色列执事医疗中心和达纳法尔伯癌研究所（Harvard Medical School）的DanaConess医疗中心和Dana-Farber癌症研究所（Harvard Medical School）进行过博士后培训，并在细胞水平的整个动物生理学和机械研究方面都有经验。她的职业发展计划将尖端技术的培训与职业发展活动结合在一起，以促进她向独立的过渡，包括正式的课程工作，参加科学会议以及在其研究领域具有专业知识的联合导师委员会的支持。该计划使Wrann博士能够在运动引起的突触可塑性和认知方面的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员和教师导师，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。认知障碍是由各种疾病引起的，例如老化，神经退行性疾病，例如阿尔茨海默氏病，以及精神病和神经发育障碍，例如精神分裂症或自闭症。与此类障碍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，有效的治疗选择严重不足，主要是由于缺乏治疗靶标。在各种啮齿动物模型以及临床研究中，运动与改善的认知功能，尤其是学习和记忆有关。但是，为了从运动干预措施中得出可药物的目标，需要更深入地了解调节运动诱导的改善认知的分子机制。我的初步研究将FNDC5（含5个含量5）确定为一种有前途且新颖的调节剂对运动诱导的认知益处的调节剂（Wrann等人，细胞代谢，2013年）。基于这些数据，我假设FNDC5是将运动与BDNF表达和突触可塑性联系起来的关键调节剂，从而将其与认知功能的改善联系起来。该提议的目的是严格检验该假设，并通过整合细胞培养中的机理实验，遗传小鼠模型中的功能电生理学和形态学研究以及行为测试来评估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AIM 1中，我将检验以下假设：运动诱导的BDNF表达需要FNDC5，从而改善了认知，这是FNDC5调节突触可塑性的AIM 2，并且在AIM 3中，FNDC5可以在认知能力下降的鼠模型中提高认知功能。这些实验的成功完成将更好地理解分子机制，该机制会影响突触可塑性并改善认知功能。此外，它为FNDC5如何在认知下降的鼠模型中改善认知功能建立了一个框架，这可能代表了一种治疗这些疾病的新型治疗方法。