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.

项目概要 我的长期目标是制定一个独立的研究计划，调查如何改变 正常的记忆和情绪处理会导致精神疾病的发生，而 导致从正常向病理转变的机制。迄今为止，我主要使用我的行为 和分子神经科学培训，以研究恐惧记忆和恐惧记忆背后的分子机制 外部环境压力源在这些过程的调节中的作用。内部事件，包括严重的 疾病和心脏病发作也经常导致焦虑、抑郁和创伤后应激障碍 (PTSD) 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，成员包括我的导师 Jelena Radulovic 博士、 分子和行为神经科学和神经免疫学专家，以及免疫学和神经免疫学专家 心血管疾病模型分别为斯蒂芬·米勒博士和道格拉斯·洛索多博士。有了这些 顾问，我将接受免疫学技术和概念的培训，学习手术方法 诱发心肌梗塞，并且在Radulovic博士的指导下，我将接受以下方面的指导 与焦虑和恐惧的动物模型相关的问题，以及对概念的具体指导 神经免疫学和其他分子技术。 该项目旨在研究特定大脑区域的细胞因子信号传导对 出现焦虑和过度恐惧。为此，我将开发一个新模型，整合手术模型 心脏病发作（心肌梗塞，MI）触发全身细胞因子反应，其行为模型 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 雄性和雌性小鼠这些行为改变的相关性和原因。在目标 1 中，我将确定 心肌梗死后出现焦虑和过度恐惧。目标 2 将确定 MI 后细胞因子的失调 与焦虑和恐惧相关的大脑区域。最后，目标 3 将检查细胞因子依赖性细胞内 介导焦虑和恐惧增加的分子信号机制。在所有的实验中我都会 同时研究雄性和雌性小鼠。我假设焦虑和恐惧加剧将是一个结果 心肌梗死的发生，在心肌梗死发生后数周和数月内出现并持续。在这些行为改变的同时，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 (PTSD) 的具体病因学以及更多 一般问题是，在慢性外部压力源之后，相同的机制是否会介导 PTSD。 在这个项目的指导阶段，我将执行目标 1 和 2，这将为 实验数据以及获得的技能和知识，对于我将在独立阶段 确定细胞因子介导的 JAK/STAT 信号在 MI 后焦虑出现中的激活和作用 障碍和创伤后应激障碍。该项目将提供一个框架来维持我正在进行的研究， 独立的研究生涯。我预计该研究产生的数据有两个主要方向 项目将是（1）对行为或信号传导中出现的性别差异进行详细的机制研究 MI 后的变化，以及 (2) 细胞因子信号传导在从应激的急性适应性效应转变为应激效应的过程中的作用 慢性、适应不良综合征。 我在该项目指导阶段的培训将在 Jelena 博士的实验室进行 拉杜洛维奇是西北大学精神病学和行为科学系的教授。在这里，我有 获得许多资源，包括协作讨论、进行会议所需的设备 针对培训广度和深度以及专业发展的实验、研讨会和课程 机会，包括研讨会和研究报告。此外，我将有权访问资源 以及我的顾问和顾问小组成员 Drs. 的专业知识。 Miller 和 Losordo，用于细胞因子分析和 分别是心肌梗塞和组织学。 通过这个项目获得的培训，我将学习免疫学、外科和其他知识 行为和分子神经科学技能，开发多学科模型以用于后续研究 项目，并生成数据作为未来研究方向的基础。因此，在指导结束时 阶段，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。