The role of macrophages in neonatal nociceptive priming

项目概要/摘要：早期生活的侮辱有能力“启动”躯体感觉系统（新生儿 引发），其改变感知外围刺激的方式。这可能会导致更糟糕的结果后， 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使用增加， 发生.更好地理解急性新生儿损伤如何促进在以后的生活中向慢性疼痛的过渡， 因此至关重要。以前的工作已经开始解剖中枢神经元和免疫成分， 有助于新生儿伤害性启动，但外周成分是大大不足的研究。已知 然而，诱导“启动”效应需要外围输入，最近的数据表明， 免疫细胞对于改变新生儿与老年受试者相比独特的伤害感受是必需的。我们 初步工作证实了最近的文献，即巨噬细胞被消融的新生儿， 表现出损伤诱导的机械超敏反应。有趣的是，巨噬细胞在 新生儿，因为他们有能力保留来自早期生活刺激的表观遗传修饰。这种表观遗传 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引发的机制。 该项目旨在通过更好地了解 外周免疫系统保留早期生命损伤的记忆，以在以后的生命中影响伤害感受。我们将测试 核心假设是急性损伤后新生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节对新生儿的发育至关重要 启动我们将通过一系列实验来验证这一点，这些实验询问巨噬细胞的必要性。 通过基因敲除策略，通过过继转移充分的巨噬细胞，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。Specific Aim 1使用我们的体外 电生理记录制剂，行为敏感性测定，以及炎症的测量， 小鼠（MaFIA小鼠）或过继转移巨噬细胞，以确定新生儿 切口对外周敏化和伤害性引发的影响。Specific Aim 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 发育调节的组蛋白脱乙酰酶SIRT 1调节新生儿伤害性启动。为了 为了解决这些问题，一个由研究人员组成的导师团队已经组建起来，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，主要赞助商），免疫学（Deepe博士，共同赞助商）， 赞助商）和表观遗传学（Kottyan博士，共同赞助商）谁将指导和帮助我与这些具体的研究 问题研究这个导师团队还将提供所有必要的学术和科学发展， 促进了我在神经科学领域的事业总的来说，该项目将提供有关新生儿的有影响力的信息。 启动和允许我建立一个坚实的基础，为一个独立的职业生涯在疼痛生物学。

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.