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：早期生活侮辱有能力“启用”体感系统（新生儿） 启动）改变了周围刺激的方式。这可能会导致更糟的结果 后来的伤害。结果，诸如慢性疼痛和阿片类药物增加等重大临床问题可以 更好地理解急性新生儿损伤如何促进后来生活的慢性疼痛过渡是 因此至关重要。先前的工作已经开始剖析中央神经元和免疫成分 对新生儿伤害性启动的贡献，但周围成分已广为人知。我们都知道 但是，要引起“启动”效应需要外围输入，并且最新的数据表明 与老年受试者相比，这种免疫细胞对于在新生儿中独特地改变伤害感受是必要的。我们的 初步工作证实了最近的文献，即巨噬细胞被消融的新生儿，不要 证明了损伤引起的机械性超敏反应。有趣的是，巨噬细胞在 新生儿由于能够从早期生命刺激中保留表观遗传学修饰。这种表观遗传学 未成熟巨噬细胞中的脆弱性可能会提供一种驱动新生儿伤害性启动的机制。 该项目将通过更好地理解如何了解如何解决文献中的主要差距 外围免疫系统保留了早期生命损伤的记忆，以在以后的生活中引起伤害感受。我们将测试 急性损伤后新生儿巨噬细胞激活的中心假设改变了他们 神经免疫信号的表观遗传调节，这对于新生儿的发展至关重要 启动。我们将通过一系列质疑巨噬细胞的实验进行测试 通过淘汰策略，通过自适应转移的巨噬细胞充分性，并确定表观遗传 巨噬细胞内的机制可能是这种现象的基础。特定目标1使用我们的前体体 电生理记录制剂，行为敏感性的测定和炎症的测量 耗尽（黑手党小鼠）或巨噬细胞的自适应转移以确定新生儿的影响 对周围敏感性和伤害性启动的切口。特定目标2首先使用公正的测序 巨噬细胞中的策略，然后评估巨噬细胞的特异性表达是否 开发的调节组蛋白脱氧酶SIRT1可调节新生儿伤害性启动。为了 解决这些问题，一组研究人员导师已经组装了，以提供感官方面的专业知识 神经科学和新生儿伤害感受（Jankowski博士，初级赞助商），免疫学（Deepe博士，共同 赞助商）和表观遗传学（Kottyan博士，共同赞助者），他们将指导和帮助我进行这些特定的研究 研究。这支导师团队还将提供所有必要的学术和科学发展 进一步，我在神经科学领域的职业生涯。总的来说，该项目将提供有关新生儿的有影响力的信息 启动并允许我为疼痛生物学独立职业建立坚实的基础。

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