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: 8092144
• 负责人: Natalie Celia Tronson
• 金额: $ 8.77万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8092144
• 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

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）：我的长期目标是开发一个独立的研究计划，调查正常记忆和情绪处理的改变如何导致精神疾病的发展，以及导致从正常转变为病理的机制。迄今为止，我主要利用行为和分子神经科学训练来研究恐惧记忆背后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。包括严重疾病和心脏病发作在内的内部事件也经常导致焦虑、抑郁和创伤后应激障碍（PTSD）增加，然而这些内部事件后介导失调的机制仍不清楚。 为了有效地研究焦虑和恐惧的内部触发因素，我需要额外的培训和支持。因此，我组建了一个顾问小组，由我的导师 Jelena Radulovic 博士（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专家 Stephen Miller 博士和 Douglas Losordo 博士组成。在这些顾问的指导下，我将获得免疫学技术和概念的培训，学习诱发心肌梗塞的手术方法，并且在拉杜洛维奇博士的指导下，我将接受与焦虑和恐惧动物模型相关的问题的指导，以及神经免疫学概念和其他分子技术的具体指导。 该项目旨在研究特定大脑区域的细胞因子信号传导对焦虑和过度恐惧的出现的影响。为此，我将开发一个新模型，将触发全身细胞因子反应的心脏病发作（心肌梗塞，MI）手术模型与焦虑和恐惧的行为模型相结合。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的信号传导相关性以及这些行为改变的原因。在目标 1 中，我将确定 MI 后焦虑和过度恐惧的出现。目标 2 将确定心肌梗死后与焦虑和恐惧相关的大脑区域细胞因子的失调。最后，目标 3 将检查介导焦虑和恐惧增加的细胞因子依赖性细胞内分子信号传导机制。在所有实验中，我将同时研究雄性和雌性小鼠。我假设焦虑和增强的恐惧将是心肌梗死的后果，在心肌梗死后的数周和数月内出现并持续存在。在这些行为变化的同时，我预计大脑区域中介导焦虑和恐惧的促炎细胞因子也会增加。最后，我假设细胞因子依赖性 JAK/STAT 信号传导介导 MI 后的情绪和记忆失调。这些发现对于心脏病发作后创伤后应激障碍的具体病因学以及慢性外部应激源后是否相同的机制介导创伤后应激障碍这一更普遍的问题都高度相关。 在该项目的指导阶段，我将执行目标 1 和 2，这将为独立阶段的实验数据以及获得的技能和知识提供坚实的基础，在独立阶段，我将确定细胞因子介导的 JAK/STAT 信号在心肌梗死后出现的焦虑症和 PTSD 中的激活和作用。该项目将为我持续的独立研究生涯中持续进行的研究提供一个框架。我预计该项目产生的数据的两个主要研究方向将是（1）对心肌梗死后行为或信号改变中出现的性别差异进行详细的机制研究，以及（2）细胞因子信号在压力的急性适应性效应向慢性适应不良综合征转变中的作用。 我在该项目指导阶段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，我可以获得许多资源，包括协作讨论、进行实验所需的设备、培训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示。此外，我还将获得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和心肌梗塞和组织学。 通过该项目获得的培训，我将学习免疫学、外科手术以及其他行为和分子神经科学技能，开发用于后续研究项目的多学科模型，并生成作为未来研究方向基础的数据。因此，在指导阶段结束时，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绪处理的分子机制，从而导致精神疾病。 公共健康相关性：该项目基于临床观察，即大部分心脏病发作患者随后出现焦虑或创伤后应激障碍，旨在利用焦虑和恐惧的动物模型来研究引发这些精神疾病的心脏病发作后机制。我预计大脑中的炎症信号传导将在心脏病发作后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靶标。