Inflammation-Induced Behavioral Alterations: A Psychogenomic Approach

炎症引起的行为改变：心理基因组学方法

• 批准号: 8313513
• 负责人: SANDRA L RODRIGUEZ ZAS
• 金额: $ 27.74万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313513
• 关键词: Address; Alcohols; Alzheimer' s Disease; Anxiety; Autistic Disorder; Behavior; Behavior Disorders; Behavioral; Bioinformatics; Biological Process; Boxing; Brain; Calmette-Guerin Bacillus; Cells; Clinical; Communication; Data; Dementia; Development; Diagnostic; Dioxygenases; Energy Metabolism; Energy Metabolism Pathway; Epigenetic Process; Exploratory/Developmental Grant; Functional disorder; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Goals; Guanine; HIV; Hormones; Immune; Immunity; Individual; Inflammation; Inflammatory; Investigation; Knock-out; Knockout Mice; Knowledge; Knowledge Discovery; Lead; Lung; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Microglia; Modeling; Molecular; Mouse Strains; Mus; Neuroimmunomodulation; Neuropeptides; Neurosciences; Nitric Oxide; Outcome; Outcome Study; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Play; Preventive; Process; RNA; RNA Splicing; Randomized; Recovery; Regulatory Element; Regulatory Pathway; Research; Research Project Grants; Role; Saline; Schizophrenia; Serotonin; Signal Pathway; System; Systems Biology; Technology; Testing; Therapeutic; Time; Transcript; Tryptophan; United States National Institutes of Health; Variant; Wild Type Mouse; Work; addiction; age related; base; burden of illness; depressive symptoms; design; disability; genome-wide; indoleamine; innovation; insight; macrophage; multidisciplinary; nervous system disorder; prognostic; reconstruction; research study; response; tetrahydrobiopterin; therapeutic target; tool; transcription factor

DESCRIPTION (provided by applicant): Major depression is the second largest burden of disease in the developed world and a leading cause of disability. The role of inflammation in depression has been established, yet a more complete understanding of the molecular mechanisms and biological processes associated with inflammation-induced depression requires an investigation of possibilities that lie "outside the box" of individual candidate systems. The rationale of this application is to fill the void that currently exists through a genome-wide functional analysis and network reconstruction of the mechanisms of inflammation-induced depression. We will integrate our well-validated and accepted murine model of Bacillus Calmette-Guerin (BCG) induced inflammation and our indoleamine 2,3 dioxygenase knock-out (IDO KO) mice to answer two important and rate-limiting questions: Aim 1) What genes are differentially expressed in innate immune cells in BCG-induced depression? Aim 2) What are the biological functions and networks of the BCG-induced depression genes? Aim 1 will be addressed by characterizing the transcriptome profile of innate immune cells measured using RNA-Seq. We have demonstrated the three pivotal cornerstones for this proposal. First, BCG inoculation induces long-lasting depression-like behaviors that persist for at least 3 weeks. Second, BCG-induced depression is mediated by IDO activation and IDO KO mice develop inflammation just as wild-type mice, although they do not display depression-like behaviors. Third, lung and brain macrophages play a crucial role in mounting inflammatory behavioral response. Therefore, a randomized 2x2 factorial design including two treatments (BCG-challenge and saline control) and two mice strains (wild type and IDO KO) will be used. Lung macrophages and brain microglia from 12 mice per challenge-strain group, based on power analysis, will be collected 2 weeks after challenge. Subtractive and differential expression contrasts between groups will permit identification of inflammation-induced depression genes that are expressed in a long-lasting model of depression-like behavior and: 1) are independent of changes in inflammation and immunity that may contribute to recovery, and 2) are independent of baseline strain differences. Aim 2 will be addressed using abstractionist functional analyses of the genes identified in Aim 1 and gene network reconstruction. In addition to knowledge discovery, we will test concrete hypotheses on the functional signature of depression, including: serotonin, guanine-tetrahydrobiopterin nitric oxide, and energy metabolism pathways and transcription factors. Key transcripts will be confirmed using Real Time Quantitative PCR. A multidisciplinary team with expertise in neuroscience, behavior, immunity, transcriptome analysis and bioinformatics has been assembled to accomplish the proposed research. This application is submitted to the R21 program because a targeted RNA-Seq "exploratory experiment" and innovative comparison of pathways and networks are proposed. The outcomes of the proposed research are: 1) identification of molecular mechanisms including immune pathways and regulatory motifs that underlie inflammation-induced depression, 2) elucidation of the relationship between inflammation and depression, and 3) insights on related processes such as age-dependent inflammation-induced depression and other inflammation-associated neurological disorders, including anxiety, autism, schizophrenia, Alzheimer's disease and dementia caused by human immunodeficiency virus, and addictions to alcohol and drugs. PUBLIC HEALTH RELEVANCE: We already know from converging clinical and experimental data that depression develops on a background of sickness under conditions of inflammation. A comprehensive understanding of the molecular basis of inflammation-induced depression will result from this first systems biology approach to investigate the transcriptome profile using functional analysis followed by gene network reconstruction. The outcomes of this study in terms of knowledge discovery and hypothesis generation will help to develop prognostic and diagnostic tools that will lead to preventive and remedial treatments for those afflicted by inflammation-induced behavioral disorders.

描述（由申请人提供）：重度抑郁症是发达国家第二大疾病负担，也是导致残疾的主要原因。炎症在抑郁症中的作用已经确定，但要更全面地了解与炎症诱发的抑郁症相关的分子机制和生物过程，需要研究个体候选系统“盒子之外”的可能性。该应用的基本原理是通过对炎症诱发抑郁症机制的全基因组功能分析和网络重建来填补目前存在的空白。我们将整合经过充分验证和接受的卡介苗 (BCG) 诱导炎症小鼠模型和吲哚胺 2,3 双加氧酶敲除 (IDO KO) 小鼠，以回答两个重要且限速的问题： 目标 1) 在 BCG 诱导的抑郁症中，哪些基因在先天免疫细胞中差异表达？目标 2) BCG 诱导的抑郁基因的生物学功能和网络是什么？目标 1 将通过表征使用 RNA 测序测量的先天免疫细胞的转录组谱来解决。我们已经展示了该提案的三个关键基石。首先，接种 BCG 会诱发持久的抑郁样行为，并持续至少 3 周。其次，BCG 诱导的抑郁症是由 IDO 激活介导的，IDO KO 小鼠与野生型小鼠一样会出现炎症，尽管它们不表现出抑郁症样行为。第三，肺和脑巨噬细胞在增强炎症行为反应中发挥着至关重要的作用。因此，将使用随机 2x2 因子设计，包括两种治疗（BCG 攻击和盐水对照）和两种小鼠品系（野生型和 IDO KO）。根据功效分析，将在攻击后 2 周收集来自每个攻击菌株组 12 只小鼠的肺巨噬细胞和脑小胶质细胞。组间的减法和差异表达对比将允许鉴定炎症诱导的抑郁基因，这些基因在抑郁样行为的长期模型中表达，并且：1）独立于可能有助于恢复的炎症和免疫的变化，2）独立于基线应变差异。目标 2 将通过对目标 1 中确定的基因进行抽象功能分析和基因网络重建来解决。除了知识发现之外，我们还将测试有关抑郁症功能特征的具体假设，包括：血清素、鸟嘌呤-四氢生物蝶呤、一氧化氮、能量代谢途径和转录因子。关键转录本将使用实时定量 PCR 进行确认。一支在神经科学、行为、免疫、转录组分析和生物信息学方面具有专业知识的多学科团队已经组建完成，以完成拟议的研究。该申请被提交给 R21 计划，因为提出了有针对性的 RNA-Seq“探索性实验”以及路径和网络的创新比较。拟议研究的结果是：1）识别炎症诱发抑郁症的分子机制，包括免疫途径和调节基序，2）阐明炎症和抑郁症之间的关系，3）深入了解相关过程，例如年龄依赖性炎症诱发的抑郁症和其他炎症相关的神经系统疾病，包括焦虑症、自闭症、精神分裂症、 由人类免疫缺陷病毒引起的阿尔茨海默病和痴呆症，以及酒精和药物成瘾。 公共健康相关性：从临床和实验数据来看，我们已经知道抑郁症是在炎症条件下的疾病背景下产生的。通过使用功能分析和基因网络重建来研究转录组谱的第一个系统生物学方法，将产生对炎症引起的抑郁症的分子基础的全面理解。这项研究在知识发现和假设生成方面的成果将有助于开发预后和诊断工具，从而为那些患有炎症诱发的行为障碍的人提供预防和治疗。