Cytokine Signaling as a Mediator of Fear and Anxiety After Myocardial Infarction

细胞因子信号传导作为心肌梗死后恐惧和焦虑的调节剂

• 批准号: 8235843
• 负责人: Natalie Celia Tronson
• 金额: $ 8.86万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-04 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235843
• 关键词: Acute; Adult; Affect; American; Americas; Amygdaloid structure; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Anxiety Disorders; Behavior; Behavioral; Behavioral Model; Behavioral Sciences; Biochemical; Biological Assay; Brain; Brain region; Cardiovascular Diseases; Chronic; Chronic stress; Clinical; Cytokine Inducible SH2-Containing Protein; Cytokine Receptors; Cytokine Signaling; Data; Development; Disease; Educational process of instructing; Educational workshop; Emotional; Emotions; Enzyme-Linked Immunosorbent Assay; Equipment; Etiology; Event; Exhibits; Female; Fright; Future; Genetic Techniques; Goals; High Prevalence; Hippocampus (Brain); Histology; Human; Hypothalamic structure; Immunologic Techniques; Immunology; Individual; Inflammatory; Interleukin-6; Janus kinase; Knowledge; Laboratories; Learning; Mediating; Mediator of activation protein; Memory; Mental Depression; Mental disorders; Mentors; Mentorship; Methods; Modeling; Molecular; Mus; Myocardial Infarction; Natural Disasters; Neurosciences; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Phase; Phosphorylation; Plasma; Play; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Prevention; Process; Proteins; Psychiatry; Regulation; Research; Research Project Grants; Resources; Retrieval; Risk; Rodent; Role; STAT3 gene; Sex Characteristics; Signal Transduction; Signal Transduction Pathway; Solid; Stress; Surgical Models; Symptoms; Syndrome; Techniques; Training; Training Support; Universities; Up-Regulation; Violence; Woman; base; career; combat; cytokine; design; environmental stressor; male; men; mortality; multidisciplinary; neuroimmunology; neuropsychiatry; novel; programs; public health relevance; research study; response; skills; stressor; transcription factor; virus genetics

DESCRIPTION (provided by applicant): My long-term goal is to develop an independent program of research investigating how alterations of normal memory and emotional processing contributes to the development of psychiatric disorders, and the mechanisms that cause the switch from normal to pathological. To date, I have primarily used my behavioral and molecular neuroscience training to investigate the molecular mechanisms underlying fear memory and the role of external environmental stressors in the modulation of these processes. Internal events, including severe illness and heart attack, also frequently cause increased anxiety, depression and PTSD, however the mechanisms that mediate dysregulation after these internal events remain unknown. In order to effectively study internal triggers of anxiety and fear, I will require additional training and support. As such, I have assembled an advisory panel consisting of my mentor, Dr. Jelena Radulovic, an expert in molecular and behavioral neuroscience and neuroimmunology, as well as experts in immunology and models of cardiovascular disease, Dr. Stephen Miller and Dr. Douglas Losordo respectively. With these consultants, I will obtain training on immunological techniques and concepts, be taught the surgical methods for induction of myocardial infarction, and, under the mentorship of Dr. Radulovic, I will receive guidance on issues related to animal models of anxiety and fear, as well as specific tutelage on concepts in neuroimmunology and additional molecular techniques. This project aims to investigate the contribution of cytokine signaling in specific brain regions to the emergence of anxiety and excessive fear. To do this I will develop a new model, integrating a surgical model of heart attack (myocardial infarction, MI) that triggers a systemic cytokine response, with behavioral models of anxiety and fear. I will use immunological and molecular neuroscience techniques to determine the signaling correlates and causes of these behavioral alterations in male and female mice. In Aim 1, I will determine the emergence of anxiety and exaggerated fear after MI. Aim 2 will determine post-MI dysregulation of cytokines in brain regions related to anxiety and fear. Finally, Aim 3 will examine the cytokine-dependent intracellular molecular signaling mechanisms that mediates increased anxiety and fear. In all experiments I will concurrently study male and female mice. I hypothesize that anxiety and enhanced fear will be a consequence of MI, emerging and persisting in the weeks and months after MI. In parallel to these behavioral changes, I expect increased pro-inflammatory cytokines in brain regions mediating anxiety and fear. Finally, I hypothesize that cytokine-dependent JAK/STAT signaling mediates emotional and mnemonic dysregulation after MI. These findings will be highly relevant both for the specific etiology of post-heart attack PTSD, and for the more general question of whether the same mechanisms mediate PTSD after chronic external stressors. During the mentored phase of this project, I will execute Aims 1 and 2, which will provide a solid basis in both experimental data, and acquired skills and knowledge, for the independent phase in which I will determine the activation and role of cytokine-mediated JAK/STAT signaling the post-MI emergence of anxiety disorders and PTSD. This project will provide a framework to sustain ongoing research in my ongoing, independent research career. I expect that two main directions for research following data generated by this project will be (1) detailed mechanistic studies of sex differences emerging in behavioral or signaling alterations after MI, and (2) the role of cytokine-signaling in the switch from acute, adaptive effects of stress, to chronic, maladaptive syndromes. My training during the mentored phase of this project will be conducted in the laboratory of Dr. Jelena Radulovic in the department of Psychiatry and Behavioral Sciences at Northwestern University. Here, I have access to many resources including collaborative discussions, the equipment required to conduct the experiment, seminars and classes for the breadth and depth of training, and professional development opportunities, including workshops and research presentations. In addition, I will have access to the resources and expertise of my consultants and advisory panelists, Drs. Miller and Losordo, for cytokine analysis and myocardial infarction and histology, respectively. Through the training gained through this project I will learn immunological, surgical, and additional behavioral and molecular neuroscience skills, develop a multidisciplinary model to use in subsequent research projects, and generate data on which to base future research directions. As such, by the end of the mentored phase, I will have the skills and knowledge to design, execute, and analyze experiments that will elucidate the molecular mechanisms by which internal and external events modulate memory and emotional processing, and thereby contribute to psychiatric disorders. PUBLIC HEALTH RELEVANCE: This project, based on the clinical observations that a large proportion of heart attack patients subsequently develop anxiety or post-traumatic stress disorder, aims to utilize animal models of anxiety and fear to investigate the post-heart attack mechanism triggering these psychiatric disorders. I expect that inflammatory signaling in the brain will play a major role in the development of anxiety and fear after heart attack, and that these pathways will be novel targets for treatment and prevention of anxiety and post-traumatic stress disorder.

描述（由申请人提供）：我的长期目标是制定一个独立的研究计划，调查正常记忆和情绪处理的变化如何有助于精神疾病的发展，以及导致从正常变为病理变为病理的机制。迄今为止，我主要使用我的行为和分子神经科学训练来研究恐惧记忆的分子机制以及外部环境压力源在调节这些过程中的作用。内部事件，包括严重的疾病和心脏病发作，也经常导致焦虑，抑郁和PTSD增加，但是在这些内部事件后介导失调的机制仍然未知。 为了有效研究焦虑和恐惧的内部触发因素，我将需要额外的培训和支持。因此，我组建了一个由我的导师，我的导师耶琳娜·拉多洛维奇（Jelena Radulovic）博士组成的咨询小组，他是分子和行为神经科学和神经免疫学专家，以及免疫学和心血管疾病模型的专家，斯蒂芬·米勒（Stephen Miller）博士和Dogglas Losordo博士。借助这些顾问，我将接受有关诱导心肌梗塞的外科手术方法的培训，在Radulovic博士的指导下，我将获得有关焦虑和恐惧动物模型有关的问题的指导，以及关于神经免疫性概念的特定概念以及神经免疫性概念的指导，以及其他分解。 该项目旨在调查特定大脑区域中细胞因子信号传导对焦虑和过度恐惧的出现的贡献。为此，我将开发一个新的模型，将心脏病发作的外科手术模型（心肌梗塞，MI）整合起来，该模型触发系统性细胞因子反应以及焦虑和恐惧的行为模型。我将使用免疫学和分子神经科学技术来确定雄性和雌性小鼠这些行为改变的信号传导相关性和原因。在AIM 1中，我将确定MI之后的焦虑和夸张的恐惧的出现。 AIM 2将确定与焦虑和恐惧有关的大脑区域中细胞因子失调后的失调。最后，AIM 3将检查细胞因子依赖性细胞内分子信号传导机制，这些机制介导了增加的焦虑和恐惧。在所有实验中，我将同时研究雄性和雌性小鼠。我假设焦虑和加剧的恐惧将是MI的结果，在MI之后的几周和几个月内出现和持续。与这些行为变化并行，我期望介导焦虑和恐惧的大脑区域的促炎细胞因子增加。最后，我假设细胞因子依赖性的jak/stat信号传导介导MI后的情绪和助记符失调。这些发现将与心脏后攻击PTSD的特定病因高度相关，以及对于慢性外部压力源后相同机制是否介导PTSD的更普遍的问题。 在该项目的指导阶段，我将执行目标1和2，这将在实验数据和获得的技能和知识中为独立阶段提供扎实的基础，在这些阶段中，我将确定细胞因子介导的JAK/STAT的激活和作用和作用，这表明焦虑症和PTSD的焦虑症后出现后出现。该项目将提供一个框架，以维持我正在进行的独立研究生涯中的正在进行的研究。我预计该项目产生的数据的两个主要方向将是（1）MI后行为或信号变化中出现的性别差异的详细机理研究，以及（2）细胞因子信号在从压力的急性，适应性效应转变为慢性，适应不良综合症的转变中的作用。 我在该项目的指导阶段进行的培训将在西北大学精神病学和行为科学系Jelena Radulovic博士的实验室进行。在这里，我可以访问许多资源，包括协作讨论，进行实验所需的设备，用于培训的广度和深度的研讨会和课程以及专业发展机会，包括研讨会和研究演讲。此外，我将可以访问我的顾问和咨询小组成员Drs的资源和专业知识。 Miller和Losordo，分别用于细胞因子分析以及心肌梗塞和组织学。 通过该项目获得的培训，我将学习免疫，外科手术和其他行为和分子神经科学技能，开发出一种多学科模型，用于随后的研究项目，并生成有关以未来研究方向为基础的数据。因此，到指导阶段结束时，我将拥有设计，执行和分析实验的技能和知识，这些实验将阐明内部和外部事件调节记忆和情感处理的分子机制，从而有助于精神疾病。 公共卫生相关性：该项目基于临床观察结果，即大部分心脏病患者随后患上焦虑或创伤后应激障碍，旨在利用焦虑动物模型和恐惧来调查触发这些精神病的心脏攻击机制。我预计大脑中的炎症信号传导将在心脏病发作后的焦虑和恐惧的发展中发挥重要作用，并且这些途径将成为治疗和预防焦虑和创伤后应激障碍的新颖目标。