The role of macrophages in neonatal nociceptive priming

巨噬细胞在新生儿伤害性启动中的作用

• 批准号: 10395956
• 负责人: Adam John Dourson
• 金额: $ 1.77万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2023-01-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395956
• 关键词: ATAC-seq; Acute; Acute Pain; Address; Adolescence; Adolescent; Adoptive Transfer; Adult; Affect; Animals; Apoptosis; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Biology; Cardiac Myocytes; Cell physiology; Cells; Childhood; Clinical; Data; Development; Electrophysiology (science); Epigenetic Process; Foundations; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Histone Deacetylase; Histones; Hypersensitivity; Immune; Immune response; Immune system; Immunology; In Vitro; Inflammation; Inflammatory; Injections; Injury; Interferon Type II; Interleukin-1 beta; Interleukin-10; Interleukin-6; Knock-out; Knowledge; Lead; Life; Link; Lipopolysaccharides; Literature; Long-Term Effects; Measures; Mechanics; Memory; Mentors; Methodology; Modification; Mus; Muscle; Neonatal; Neonatal Intensive Care Units; Nerve Growth Factors; Nervous system structure; Neuroimmune; Neuroimmunomodulation; Neurons; Neurosciences; Nociception; Nociceptors; Outcome; Pain; Pain Research; Patients; Peripheral; Play; Preparation; Probability; Procedures; Production; Public Health; Reporting; Research; Research Personnel; Role; SIRT1 gene; Series; Signal Transduction; Solid; Spinal Ganglia; Stimulus; Surgical incisions; System; Techniques; Testing; Time; Tissues; Transcriptional Regulation; Transgenic Animals; United States National Institutes of Health; Work; XCL1 gene; behavioral response; behavioral sensitization; career; cell type; chronic pain; critical period; epigenetic regulation; epigenome; experience; experimental study; immunoregulation; injured; innovation; knockout animal; macrophage; neonatal injury; neonate; novel; opioid use; pain chronification; postnatal; postnatal development; research study; response; sensory neuroscience; somatosensory; transcriptome sequencing

Project Summary/Abstract: Early life insults have the ability to “prime” the somatosensory system (neonatal priming) which changes the way peripheral stimuli are perceived. This can lead to worse outcomes after an injury later in life. As a result, significant clinical problems such as chronic pain and increased opioid use can occur. A better understanding of how acute neonatal injury facilitates the transition to chronic pain later in life is therefore crucial. Previous work has begun to dissect the central neuronal and immune components that contribute to neonatal nociceptive priming, but the peripheral component is vastly understudied. It is known however that a peripheral input is required for the “priming” effect to be induced and more recent data suggests that immune cells are necessary for altering nociception uniquely in neonates compared to older subjects. Our preliminary work confirms recent literature that neonates in which macrophages are ablated, do not demonstrate injury-induced mechanical hypersensitivity. Interestingly, macrophages are also unique in neonates as they have the ability to retain epigenetic modifications from early life stimulation. This epigenetic vulnerability in immature macrophages may provide a mechanism that drives neonatal nociceptive priming. This project will aim to answer the major gaps in the literature by providing a better understanding of how the peripheral immune system retains a memory of early life injury to effect nociception later in life. We will test the central hypothesis that the activation of neonatal macrophages following acute injury alters their epigenetic regulation of neuroimmune signals which is critical for the development of neonatal priming. We will test this through a series of experiments that interrogate the necessity of macrophages through knockout strategies, sufficiency of macrophages through adoptive transfer, and determine epigenetic mechanisms within macrophages that may underlie this phenomenon. Specific Aim 1 uses our ex vivo electrophysiological recording preparations, assays of behavioral sensitivity, and measures of inflammation in mice with depletion (MaFIA mice) or adoptive transfer of macrophages to determine the effects of neonatal incision on peripheral sensitization and nociceptive priming. Specific Aim 2 first uses unbiased sequencing strategies in macrophages, and then evaluates whether macrophage specific expression of the developmentally regulated histone deacytalase, SIRT1, modulates neonatal nociceptive priming. In order to address these questions, a team of researcher mentors have been assembled to provide expertise in sensory neuroscience and neonatal nociception (Dr. Jankowski, primary sponsor), immunology (Dr. Deepe, co- sponsor) and epigenetics (Dr. Kottyan, co-sponsor) who will instruct and help me with these specific research studies. This team of mentors will also provide all of the necessary academic and scientific development to further my career in the neurosciences. Collectively, this project will provide impactful information on neonatal priming and allow me to establish a solid foundation for an independent career in pain biology.

项目摘要/摘要：早期生活中的侮辱有能力“启动”躯体感觉系统(新生儿 启动)，这改变了感知外周刺激的方式。这可能会导致更糟糕的结果 在以后的生活中受伤。因此，严重的临床问题，如慢性疼痛和阿片类药物的使用增加可能 发生。更好地理解急性新生儿损伤如何促进晚年向慢性疼痛的过渡 因此至关重要。之前的工作已经开始解剖中枢神经元和免疫组件， 有助于新生儿伤害性启动，但对外周成分的研究还很少。这是众所周知的 然而，外周输入是诱导“启动”效应所必需的，而最近的数据表明 与年龄较大的受试者相比，免疫细胞对于改变新生儿独特的伤害性感受是必要的。我们的 初步工作证实了最近的文献，即巨噬细胞被切除的新生儿不会 表现出损伤导致的机械过敏症。有趣的是，巨噬细胞在 新生儿，因为他们有能力保留早期生命刺激的表观遗传修饰。这种表观遗传学 未成熟巨噬细胞的脆弱性可能提供了一种驱动新生儿伤害性启动的机制。 这个项目的目的是通过更好地理解 外周免疫系统保留了早期生命损伤的记忆，以影响后来的生命伤害。我们将测试 中心假说是急性损伤后新生儿巨噬细胞的激活改变了它们的 神经免疫信号的表观遗传调控对新生儿发育至关重要 引爆。我们将通过一系列询问巨噬细胞必要性的实验来验证这一点。 通过基因敲除策略，通过过继转移巨噬细胞的充分性，并确定表观遗传学 巨噬细胞内的机制可能是这种现象的基础。特定目标1使用我们的体外 电生理记录准备、行为敏感性分析和炎症测量 用耗竭的小鼠(黑手党小鼠)或过继转移巨噬细胞来确定对新生儿的影响 切开外周敏化和伤害性引爆。《特定目标2》首次使用无偏测序 策略，然后评估巨噬细胞特异性表达的 发育调节组蛋白脱氨酶，SIRT1，调节新生儿伤害性启动。为了 为了解决这些问题，已经组建了一个研究人员导师团队，提供感官方面的专业知识 神经科学和新生儿伤害学(Jankowski博士，主要赞助商)，免疫学(Deepe博士，联合 和表观遗传学(Kottyan博士，共同发起人)，他们将指导和帮助我进行这些具体的研究 学习。这个导师团队还将提供所有必要的学术和科学发展，以 进一步发展我在神经科学领域的事业。总体而言，该项目将提供有关新生儿的有影响力的信息 并让我为在疼痛生物学领域的独立职业生涯奠定坚实的基础。

项目成果

Genetic and epigenetic mechanisms influencing acute to chronic postsurgical pain transitions in pediatrics: Preclinical to clinical evidence.

• DOI: 10.1080/24740527.2021.2021799
• 发表时间: 2022
• 期刊: CANADIAN JOURNAL OF PAIN-REVUE CANADIENNE DE LA DOULEUR
• 影响因子: 2.4
• 作者: Dourson, Adam J.;Willits, Adam;Raut, Namrata G. R.;Kader, Leena;Young, Erin;Jankowski, Michael P.;Chidambaran, Vidya
• 通讯作者: Chidambaran, Vidya