Mechanisms Underlying Treatment-Resistant Depression and Anxiety in Mouse Models

职位描述(申请人提供)：我的职业目标是独立进行基础研究和最终的翻译研究，并培养研究生和医学生。我的主要研究兴趣和我职业生涯的长期目标是改进精神疾病的治疗，如严重抑郁障碍。为此，我计划使用行为学方法在药物和/或基因改变的小鼠中建立疾病模型和治疗方法。然后，我计划使用细胞、分子和基于电路的技术的组合来确定这些小鼠模型中潜在的疾病原因和成功的治疗方法。这项建议的直接目标是确定信号通路(TGFbeta)在调节抗抑郁药物反应中的重要性，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的实践培训，以制造突变小鼠，以及体内药物操作的使用。这些部分是必要的培训，不仅是为了执行设计的研究计划，也是作为我的独立实验室所需的实用技能。与研究性培训相辅相成的是一个更具智能性的培训目标，旨在增进我对神经精神病学翻译方法的理解。我的最终目标是最终将我的基础研究进展带入临床环境，哥伦比亚大学/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，以及我将在合作中直接与内科科学家互动的环境 努力。这一培训部分将包括与内科科学家的定期会议和课程工作。研究项目简介：阐明抑郁症的神经生物学基础和确定改进的治疗方法是现代科学面临的首要挑战之一。严重的抑郁症影响了2-5%的美国人口，情绪障碍影响了世界7%的人口，并跻身于前十大致残原因之列。然而，抑郁症的表现是高度异质性的，并经常表现出与其他精神和躯体缺陷的高发病率。常用的治疗方法，如选择性5-羟色胺再摄取抑制剂(SSRI)，并不理想，因为只有一小部分患者获得缓解。在这项提案中，我们通过使用一种新的策略来模拟动物的治疗耐药性来评估这个问题。我们发现，在对SSRI治疗有反应者的齿状回中，TGFbeta信号显著激活，但在未治疗的动物或无反应者中没有。基于这一初步数据和之前的研究，这项建议的目标是进一步了解 动物治疗耐药的分子机制。具体地说，我们将全面研究齿状回中TGFbeta信号在介导氟西汀效应中的作用，并询问TGFbeta信号的激活是否能够将无应答者转变为应答者。目的1-确定氟西汀对治疗反应和治疗无效的齿状回中转化生长因子β信号的影响目标2-确定齿状回中是否需要转化生长因子β信号来调节抗抑郁药物的作用目的3-确定齿状回中的转化生长因子β信号是否可以将无反应者转化为抗抑郁治疗的应答者 公共卫生相关性：这项建议的目标是显著提高人们对为什么许多常用的抗抑郁药只在一小部分受试者中缓解抑郁症状的理解。对为什么抗抑郁药并不总是有效的更好的基础知识可能会导致新的补充治疗的潜在治疗目标，这可能是对现有药物的改进。

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 PUBLIC HEALTH RELEVANCE: The goal of this proposal is to significantly advance the understanding of why many commonly used antidepressants yield a remission from depressive symptoms in only a subset of subjects. A better basic knowledge of why antidepressants don't always work could lead to potential therapeutic targets for new supplemental treatments that could be an improvement over current drugs.