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: 8538503
• 负责人: Natalie Celia Tronson
• 金额: $ 23.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538503
• 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; research study; response; skills; stressor; transcription factor; virus genetics

PROJECT SUMMARY 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.

项目摘要 我的长期目标是制定一个独立的研究计划，调查如何改变 正常记忆和情感处理有助于精神疾病的发展，以及 导致从正常转变为病理的机制。迄今为止，我主要使用了我的行为 和分子神经科学训练，以研究恐惧记忆和 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 疾病和心脏病发作，也经常引起焦虑，抑郁和PTSD的增加，但是 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器，我将需要额外的培训和 支持。因此，我组建了一个咨询小组，由我的导师Jelena Radulovic博士组成， 分子和行为神经科学和神经免疫学专家，以及免疫学专家 心血管疾病的模型，斯蒂芬·米勒（Stephen Miller）博士和道格拉斯·洛索多（Douglas Losordo）博士。与这些 顾问，我将接受有关外科手术方法的培训 为了诱导心肌梗塞，在Radulovic博士的指导下，我将获得有关的指导 与焦虑和恐惧动物模型有关的问题，以及有关概念的特定指导 神经免疫学和其他分子技术。 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。为此，我将开发一个新模型，集成了外科模型 心脏病发作（心肌梗死，密歇根州）触发全身细胞因子反应，行为模型 焦虑和恐惧。我将使用免疫学和分子神经科学技术来确定信号传导 这些行为改变的男性和雌性小鼠的相关性和原因。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将确定细胞因子的MI后失调 在与焦虑和恐惧有关的大脑区域中。最后，AIM 3将检查细胞因子依赖性细胞内 介导焦虑和恐惧的分子信号传导机制。在所有实验中，我都会 同时研究雄性和雌性小鼠。我假设焦虑和加剧的恐惧将是结果 MI，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 预计在介导焦虑和恐惧的大脑区域中促炎性细胞因子的增加。最后，我假设 依赖细胞因子的jak/stat信号传导MI后介导情绪和助攻失调。 这些发现将与心脏后攻击PTSD的特定病因高度相关，并且更多 相同机制是否在慢性外部压力源后介导PTSD的一般问题。 在该项目的指导阶段，我将执行AIM 1和2，这将在 对于我将要的独立阶段的实验数据以及获得的技能和知识 确定细胞因子介导的JAK/STAT信号的激活和作用 疾病和PTSD。该项目将提供一个框架，以维持我正在进行的，正在进行的研究 独立研究职业。我希望这两个主要方向用于研究该数据产生的数据 项目将是（1）行为或信号中出现的性别差异的详细机械研究 MI之后的改变，以及（2）细胞因子信号在从急性，自适应效应转变为的转换中的作用 慢性，适应性综合症。 我在该项目的指导阶段的培训将在Jelena博士的实验室进行。 西北大学精神病学和行为科学系的Radulovic。在这里，我有 访问许多资源，包括协作讨论，进行进行的设备 实验，研讨会和课程，以进行培训的广度和深度以及专业发展 机会，包括研讨会和研究演讲。此外，我将可以访问资源 以及我的顾问和咨询小组成员的专业知识，博士。 Miller和Losordo，用于细胞因子分析和 心肌梗塞和组织学分别。 通过通过该项目获得的培训，我将学习免疫，外科和其他 行为和分子神经科学技能，开发一个多学科模型，用于随后的研究 项目，并生成以未来研究方向为基础的数据。因此，到指导的结尾 阶段，我将拥有设计，执行和分析实验的技能和知识，以阐明 内部和外部事件调节记忆和情感处理的分子机制， 从而导致精神疾病。