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

• 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
• 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

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和最终转化研究，并培养研究生和医学生。我的主要研究兴趣，以及我职业生涯的长期目标，是改善精神疾病的治疗，如重度抑郁症。为此，我计划使用行为方法在哺乳动物和/或遗传改变的小鼠中建立疾病和治疗模型。然后，我还计划使用细胞、分子和基于电路的技术相结合，以确定这些小鼠模型中疾病原因和成功治疗的潜在机制。该提案的直接目标是确定信号通路（TGF β）的重要性，该信号通路在难治性抑郁症和焦虑症的动物模型中未能被激活，介导抗抑郁反应。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，主要包括基因靶向技术的实践培训，以制造突变小鼠和体内药理学操作的利用。这些组成部分是必要的培训，不仅要按照设计执行研究计划，而且要作为我的独立实验室所需的实用技能。补充研究训练将是一个更智能的训练目标，旨在提高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，以及我将直接与医生-科学家合作互动的环境。 努力这一培训部分将包括与医生-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最大挑战之一。严重形式的抑郁症影响2-5%的美国人口，情绪障碍影响7%的世界人口，并在十大残疾原因中排名。 然而，抑郁症是高度异质性的表现，并经常表现出与其他精神和躯体缺陷的高共病率。常用的治疗方法，如选择性5-羟色胺再摄取抑制剂（SSRIs），并不理想，因为只有一部分患者达到缓解。在这个建议中，我们开始通过使用一种新的策略来评估这个问题，以模拟动物的治疗耐药性。我们发现，SSRI治疗的应答者齿状回中TGF β信号显著激活，但未治疗的动物或无应答者中没有。基于这些初步数据和以前的研究，本提案的目标是进一步了解 动物耐药性的分子机制。具体来说，我们将全面研究齿状回中TGF β信号传导在介导氟西汀作用中的作用，并询问TGF β信号传导的激活是否能够将治疗无应答者转化为应答者。提案标题：小鼠模型中难治性抑郁和焦虑的机制目的1 -确定氟西汀对治疗应答者和非应答者的齿状回中的TGF β信号传导的影响。目的2 -确定齿状回中的TGF β信号传导是否是介导抗抑郁药的作用所必需的。确定齿状回中的TGF β信号激活是否可以将抗抑郁药治疗的无应答者转化为应答者