Engineering Models of Neuroimmune Sensitization to Elucidate Mechanisms of Pain Resolution

在美国，慢性疼痛影响高达20%的所有人，并且涉及外周组织（即皮肤、肌肉）、脊髓和大脑的变化。目前的慢性疼痛模型无法复制身体的复杂性，因此无法开发出适用于患者的新治疗方法。 该项目旨在设计新的台式模型，准确地模仿慢性疼痛的特点在周边;并增加慢性疼痛如何发展，维持和解决的理解。这项研究还将探索免疫系统如何帮助解决慢性疼痛。项目实施包括综合教育/外联活动，旨在提高不同人群和不同年龄学生对科学的兴趣。 该团队将把原代神经元培养纳入内布拉斯加大学林肯分校的组织工程课程，以降低进入神经工程领域的门槛。 此外，该团队将开发和实施有趣的互动课程和实验室，向中学生和Osher终身学习研究所成员（为50岁以上的人提供服务）教授生物医学工程和慢性疼痛。 本研究的目标是创建体外模型，复制慢性疼痛期间外周组织中存在的生理复杂性，以增加对机制的理解并确定治疗外周疼痛的新靶点。疼痛最常见的外周特征是疼痛神经元的刺激阈值降低，称为伤害感受器超敏反应。在动物模型中已证明有效性的临床试验中，疼痛治疗剂的转化失败率很高，这促使人们需要更有效的工具和机制知识。精确模拟慢性疼痛外周特征的初级感觉神经元和相关细胞的体外模型对于理解慢性疼痛的机制和开发新的治疗靶点具有很大的希望。然而，迄今为止，大多数降低的神经元阈值或伤害感受器超敏性的体外模型具有局限性。目的1：构建一个生理学相关的伤害感受器超敏反应多室模型，并验证其对伤害性刺激的反应。目的2建立伤害感受器超敏反应的神经免疫特异性模型，通过在神经突隔室中共培养不同表型的巨噬细胞来测试抗炎巨噬细胞的消退机制。外周疼痛功能的体外模型在增强对疼痛驱动机制和治疗转化效果的理解方面具有很大的希望。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Chronic pain affects up to 20% of all people in the United States and involves changes in peripheral tissues (i.e. skin, muscle), the spinal cord, and the brain. Current models of chronic pain fail to replicate the complexity of the body and thus fail to develop new treatments that translate to patients. This project seeks to engineer new bench top models that accurately mimic the features of chronic pain in the periphery; and increase understanding of how chronic pain develops, is maintained, and can be resolved. This research will also explore how the immune system can help resolve chronic pain. Project implementation includes integrated education/outreach activities designed to increase interest in science among diverse populations and across students of multiple ages. The team will incorporate primary neuronal culture into the Tissue Engineering curriculum at the University of Nebraska-Lincoln to lower the barrier to entry in the neural engineering field. Further, the team will develop and implement fun, interactive lessons and labs to teach middle school students and Osher Lifelong Learning Institute members (serving people over the age of 50) about biomedical engineering and chronic pain. The goal of this research is to create in vitro models that replicate the physiological complexity in peripheral tissue present during chronic pain to increase mechanistic understanding and identify novel targets to treat peripheral pain. The most common peripheral feature of pain is a lowered stimulation threshold of painful neurons termed nociceptor hypersensitivity. The high rate of translational failure of pain therapeutics in clinical trials that have demonstrated efficacy in animal models motivates the need for more effective tools and mechanistic knowledge. In vitro models of primary sensory neurons and associated cells that accurately mimic the peripheral features of chronic pain hold great promise to understand mechanisms of chronic pain and develop new treatment targets. However, to date, most in vitro models of lowered neuronal thresholds or nociceptor hypersensitivity have limitations. Objective 1 will engineer a physiologically relevant multi-compartment model of nociceptor hypersensitivity and validate its response using noxious stimuli. Objective 2 will establish a neuroimmune-specific model of nociceptor hypersensitization to test anti-inflammatory macrophage mechanisms of resolution by co-culturing macrophages of varying phenotypes in the neurite compartments. In vitro models of peripheral pain features hold great promise to enhance understanding of the mechanisms driving pain and translational efficacy of treatments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.