Immunological contributions to Age-dependent variations in response to cutaneous inflammation and the programming of later life pain

该项目侧重于从出生到成年期间炎症反应的年龄依赖性改变。新生儿对疼痛的反应是不成熟的，与成年人的反应有很大不同。生命的早期代表了神经系统高度依赖活动的重塑时期。这对疼痛处理有特别明显的影响。新生儿对疼痛的反应是夸张的、不协调的，而且往往是不适当的。疼痛阈值较低，然而，尽管临床不愿意承认这一点，直到最近，疼痛在意识层面上得到了重视。早期生活中的疼痛能够改变一个人在以后的生活中对疼痛的反应。在动物模型和临床人群中都显示，新生儿手术损伤或炎症会改变整个生命过程中的疼痛阈值，并导致成年后对进一步损伤的反应增强。炎症性疼痛是最常见的病理性疼痛，新生儿和成年人一样容易受到伤害。然而，新生儿对炎症刺激的反应在成人和新生儿之间是不同的。实验性的炎性原，如卡拉胶，在成人中引起组织肿胀和疼痛过敏，在没有疼痛的新生儿中引起组织肿胀，但有能力“编程”发育中的神经系统以应对未来的事件。结合体内、离体和体外方法，该项目将试图描述成人和新生儿在对炎性原的反应方面的差异，并确定对此负责的关键分子机制。我们将研究不同年龄的大鼠（从出生后第一天到成年）炎症部位募集的细胞类型，我们将研究这些细胞的表型和转录组，试图确定以年龄依赖性方式调节的关键分子途径，这可能解释急性炎症反应的差异，以及可能引起神经元行为长期变化的过程。

This project focuses on age-dependent alterations in inflammatory responses from birth to adulthood. Neonatal responses to pain are immature and significantly different to those seen in adults. Early life represents a period of intense activity-dependent remodelling of the nervous system. This has a particularly acute effect with regards to pain processing. Neonatal responses to pain are exaggerated, uncoordinated and often inappropriate. Pain thresholds are lower, yet, despite clinical reluctance to acknowledge this until recently, pain is appreciated at a conscious level. Pain in early life is capable of altering pain responses throughout the rest of an individuals life. Neonatal surgical injury or inflammation has been shown in both animal models and in clinical populations to alter pain thresholds through the life-course and result in enhanced responses to further injury in adulthood. Inflammatory pain is the most common form of pathological pain conditions and neonates are just as vulnerable to them as adults. However the response of neonates to inflammatory stimuli is different between adults and neonates. Experimental inflammogens such as carrageenan which evoke tissue swelling and painful hypersensitivity in adults provoke tissue swelling in the absence of pain in neonates but has the capability to "programme" the developing nervous system to future events. Using a combination of in vivo, ex vivo and in vitro approaches this project will seek to characterise the differences between adults and neonates in terms of responses to inflammogens as well as identifying key molecular mechanisms that are responsible for this. We will be investigating the types of cells recruited to sites of inflammation in different ages of rats (from postnatal day 1 until adulthood), we will investigate the phenotype and transcriptome of these cells to try and identify key molecular pathways which are regulated in an age-dependent manner that may explain the differences in acute inflammatory responses as well as processes that can provoke long-term changes in neuronal behaviour.