Peripheral Mechanisms of Sensory Neuron Plasticity

描述(由申请人提供)： 本申请表是关于导师研究科学家发展奖(K01)的申请。这项研究的长期目标是研究神经免疫相互作用在感觉神经元可塑性的外周机制中的作用。概述了该项目的具体目标。 1)确定在IB4结合神经元消融后，受影响神经中促炎症细胞因子水平改变所介导的存活感觉神经元的反应特性的改变是否导致伤害性阈值的恢复(Vulchanova等人，2001年)。这些研究将采用免疫组织化学、梳理纤维记录单个单位的活动、反义治疗的行为分析以及基于蛋白质组学的差异表达分析。 2)确定脊髓神经结扎(SNL)后损伤神经中促炎症细胞因子的上调是否与完整感觉神经元的变化有关，这可能是神经病理性疼痛发生的机制之一。这个特定的目的将通过免疫组织化学、反义治疗的行为分析和基于蛋白质组学的差异表达分析来解决。 3)确定炎症诱导的肠壁细胞因子上调是否与内脏脊髓感觉神经元的反应特性改变有关。这些研究将采用免疫组织化学、梳理纤维记录单个单位的活动和反义治疗。 这些研究将阐明促炎细胞因子在感觉过敏状态中的作用，并可能导致确定慢性疼痛治疗的新靶点。该项目将使候选人获得蛋白质组学和电生理学方面的专业知识，并将为在代表不足的内脏疼痛领域建立独立的研究计划提供理论和实验基础。

DESCRIPTION (provided by applicant): This application is for a Mentored Research Scientist Development Award (K01). The broad long-term objective of the proposed studies is to examine the role of neuroimmune interactions in peripheral mechanisms of sensory neuron plasticity. Outlined are the specific aims of this project. 1) Determine if changes in the response properties of surviving sensory neurons, mediated by altered levels of proinflammatory cytokines in the affected nerve, underlie the recovery of nociceptive thresholds after ablation of IB4-binding neurons (Vulchanova et al, 2001). These studies will employ immunohistochemistry, teased-fiber recording of single unit activity, behavioral analysis of anti-sense treatment, and proteomics-based differential expression analysis. 2) Determine if upregulation of proinflammatory cytokines in the injured nerve after Spinal Nerve Ligation (SNL) is associated with changes in intact sensory neurons that may underlie mechanisms involved in the development of neuropathic pain. This specific aim will be addressed using immuno-histochemistry, behavioral analysis of antisense treatment, and proteomics-based differential expression analysis. 3) Determine if inflammation-induced upregulation of cytokines in the intestinal wall is associated with altered response properties of visceral spinal sensory neurons. These studies will employ immunohistochemistry, teased-fiber recording of single-unit activity, and antisense treatment. These studies will elucidate the role of proinflammatory cytokines in states of sensory hypersensitivity and may lead to identifying new targets for chronic pain therapies. The project will allow the candidate to acquire expertise in proteomics and electrophysiology and will provide theoretical and experimental foundation for establishing independent research program in the underrepresented field of visceral pain.