Mechanisms Underlying Treatment-Resistant Depression and Anxiety in Mouse Models

小鼠模型中难治性抑郁和焦虑的机制

基本信息

批准号：
8509029
负责人：
BENJAMIN A SAMUELS
金额：
$ 17.3万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-11 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509029
关键词：
Activin Receptor Activins Affect Animal Model Animals Antidepressive Agents Anxiety Basic Science Behavioral Biochemical Biological Assay Chronic Clinical Clinical Research Comorbidity Complement Complex Corticosterone DNA Microarray Chip Data Disease Disease model Disease remission Environment Exhibits Face Fluoxetine Gene Expression Gene Targeting Genes Goals Heterodimerization In Situ Hybridization Individual Infusion procedures Inhibin A Knowledge Laboratories Lead Major Depressive Disorder Mediating Medical Students Mental Depression Mental disorders Modeling Molecular Mood Disorders Mus Mutant Strains Mice Neurobiology Neurosciences Patients Pharmaceutical Preparations Phosphorylation Physicians Population Prozac Psychiatric therapeutic procedure Psychiatry Publishing Rattus Research Research Project Grants Research Training Resistance Reverse Transcriptase Polymerase Chain Reaction Role Science Scientist Selective Serotonin Reuptake Inhibitor Series Signal Pathway Signal Transduction Signaling Protein Site Societies Techniques Technology Testing Therapeutic Training Transforming Growth Factor beta Translational Research Work activin A base career cohort dentate gyrus depressive symptoms design disability graduate student granule cell improved in vivo interest meetings mouse model neuropsychiatry new therapeutic target receptor receptor binding research study response skills translational approach

项目摘要

DESCRIPTION (provided by applicant): My career goal is to independently conduct basic and eventually translational research and train graduate and medical students. My main research interest, and the long-term goal of my career, is to improve treatments of psychiatric illnesses such as major depressive disorder. To this end, I plan to model disease and treatment in pharmacologically and/or genetically altered mice using behavioral approaches. I plan to then also use a combination of cellular, molecular and circuit-based techniques to determine the mechanisms underlying disease causes and successful treatments in these mouse models. The immediate goals for this proposal are to define the importance of a signaling pathway (TGFbeta), which fails to be activated in animal models of treatment-resistant depression and anxiety, in mediating the antidepressant response. My main expertise is in molecular, cellular and behavioral approaches to neuroscience. There are multiple major components of the training plan, mainly consisting of practical training in gene targeting technology to make mutant mice and the utilization of in vivo pharmacological manipulations. These components are necessary training to not only carry out the research plan as designed, but as practical skills tha will be required in my independent laboratory. Complementing the research training will be a more intellectual training aim designed to advance my understanding of translational approaches to neuropsychiatry. It is my ultimate goal to eventually take my basic research advances into a clinical setting, and the environment in the Department of Psychiatry at Columbia/RFMH can provide me with both the academic knowledge to implement such a goal and the surroundings in which I will interact directly with physician-scientists in a collaborative effort. This training component will consist of regular meetings with physician-scientists and coursework. Research Project Description: Elucidating the neurobiological basis of depression and determination of improved treatments is one of the foremost challenges for modern science. Severe forms of depression affect 2-5% of the U.S. population and mood disorders impact 7% of the world's population and rank among the top ten causes of disability. However, depression is highly heterogeneous in presentation and frequently exhibits high co-morbidity with other psychiatric and somatic deficits. Commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients achieve remission. In this proposal, we begin to assess this question by using a new strategy to model treatment-resistance in animals. We found significant activation of TGFbeta signaling in the dentate gyrus in responders to SSRI treatment, but not in untreated animals or non-responders. Based on this preliminary data and previous studies, the goal of this proposal is to further the understanding of molecular mechanisms underlying treatment-resistance in animals. Specifically we will fully examine the role of TGFbeta signaling in the dentate gyrus in mediating the effects of fluoxetine, and ask if activation of TGFbeta signaling is capable of converting non-responders to treatment into responders. Title of proposal: Mechanisms Underlying Treatment-Resistant Depression and Anxiety in Mouse Models Specific Aims: Aim 1 - To determine the effects of fluoxetine on TGFbeta signaling in the dentate gyrus in responders and non- responders to treatment Aim 2 - To determine if TGFbeta signaling in the dentate gyrus is required for mediating the effects of antidepressants Aim 3 - To determine if TGFbeta signaling activation in the dentate gyrus can convert non-responders to antidepressant treatment into responders

描述（由申请人提供）：我的职业目标是独立进行基础研究和最终转化研究，并培训研究生和医学生。我的主要研究兴趣和我职业生涯的长期目标是改善重度抑郁症等精神疾病的治疗。为此，我计划使用行为方法对药理学和/或基因改变的小鼠进行疾病和治疗建模。然后，我还计划结合使用细胞、分子和基于电路的技术来确定这些小鼠模型中疾病原因和成功治疗的机制。该提案的直接目标是确定信号通路 (TGFbeta) 在介导抗抑郁反应中的重要性，该信号通路在难治性抑郁和焦虑的动物模型中未能被激活。我的主要专长是神经科学的分子、细胞和行为方法。培训计划有多个主要组成部分，主要包括基因打靶技术制造突变小鼠和体内药理操作的实践培训。这些组成部分是必要的培训，不仅可以执行设计的研究计划，而且可以作为我的独立实验室所需的实用技能。对研究培训的补充将是更加智力的培训目标，旨在增进我对神经精神病学转化方法的理解。我的最终目标是最终将我的基础研究进展应用于临床，哥伦比亚/RFMH 精神病学系的环境可以为我提供实现这一目标的学术知识以及我将互动的环境直接与医师科学家合作努力。该培训部分将包括与医师科学家的定期会议和课程作业。研究项目描述：阐明抑郁症的神经生物学基础并确定改进的治疗方法是现代科学面临的首要挑战之一。严重的抑郁症影响着 2-5% 的美国人口，情绪障碍影响着世界上 7% 的人口，并跻身十大致残原因之列。然而，抑郁症的表现具有高度异质性，并且经常与其他精神和躯体缺陷表现出高度共病。常用的治疗方法，例如选择性血清素再摄取抑制剂（SSRI）并不理想，因为只有一部分患者获得缓解。在这项提案中，我们开始通过使用一种新策略来模拟动物的治疗耐药性来评估这个问题。我们发现对 SSRI 治疗有反应的动物齿状回中 TGFbeta 信号传导显着激活，但在未治疗或无反应的动物中没有显着激活。基于这些初步数据和之前的研究，该提案的目标是进一步了解动物治疗抵抗的分子机制。具体来说，我们将全面检查齿状回中 TGFbeta 信号传导在介导氟西汀作用中的作用，并询问 TGFbeta 信号传导的激活是否能够将治疗无反应者转化为反应者。提案标题：小鼠模型中难治性抑郁和焦虑的机制具体目标：目标 1 - 确定氟西汀对治疗有反应者和无反应者齿状回 TGFbeta 信号传导的影响目标 2 - 确定 TGFbeta 信号传导是否对治疗有反应介导抗抑郁药的作用需要齿状回中的 TGFbeta 信号传导激活。齿状回可以将抗抑郁治疗的无反应者转变为有反应者