Cellular Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

 描述（由申请方提供）：化疗诱导的周围神经病变（CIPN）和相关疼痛代表了患者抗癌治疗的临床相关限制 毒品目前，对于CIPN没有有效的治疗。外周感觉神经元的兴奋性增强被认为有助于CIPN的产生和进展。通过直接影响膜兴奋性，CIPN引起的化疗药物可能会增强神经元活性，从而导致神经兴奋性毒性和神经病。然而，外周感觉神经元兴奋性的变化是否是CIPN的早期形成事件尚不清楚。迄今为止，很少有外周感觉神经元直接研究化疗药物引起CIPN的细胞和分子机制的研究。在哺乳动物中进行这样的实验由于背根神经节内感觉神经元的异质性而变得复杂，背根神经节是哺乳动物中伤害感受器所在的部位，并且这些复杂生物体的实验易处理性受到限制。提交此提案的PI小组擅长研究果蝇、啮齿动物和人类外周感觉神经元中感觉转导的细胞机制。目前的建议结合了互补的专业知识，在相关的啮齿动物模型的外周疼痛与模型生物体的公正的方法，调查CIPN的细胞和分子机制。本提案的目标是证明从调查CIPN的影响中收集到的理解，在简单的模型生物体中引起外周感觉神经元上的化疗药物可以以合理的方式用于指导相关哺乳动物系统中更复杂的研究，以提供确定CIPN的细胞和分子机制的有力手段，并促进用于治疗CIPN的新镇痛剂的发现。CIPN。我们的初步结果表明，新的假设，CIPN是化疗药物的外周伤害感受器的感觉转导机制的直接影响的结果。我们通过测试三个具体目标来实现这一R21的目标：目标1;描述一种新的CIPN果蝇模型，该模型将用于指导相关哺乳动物疼痛模型的实验。目的2：明确长春碱和紫杉醇对感觉神经元功能影响的细胞和分子机制。目的3：研究外周应用长春碱和紫杉醇是否能诱导哺乳动物CIPN。本文提出的工作的重要性和意义得到了NIH/NCI最近的资助公告的支持：PA-12-083，“抗癌治疗（R21）周围神经损伤的生物机制”。预计本提案中描述的实验的成功完成将提供对CIPN基础的基本机制的关键理解，并建立一个能够使用合理和转化方法开发新的治疗策略来对抗CIPN的研究团队。

 DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) and the associated pain represent a clinically relevant limit to patient treatment with anti-cancer drugs. Currently, there is no effective treatment for CIPN. Enhanced excitability of peripheral sensory neurons is thought to contribute to the generation and progression of CIPN. By directly affecting membrane excitability, CIPN-causing chemotherapy drugs may enhance neuronal activity eventuating neuroexcitotoxicity and neuropathy. Whether a change in peripheral sensory neuron excitability is an early formative event of CIPN, though, is unknown. To date there have been few studies of peripheral sensory neurons directly investigating the cellular and molecular mechanisms by which chemotherapy drugs cause CIPN. Performing such experiments in mammals has been complicated by the heterogeneity of sensory neurons within the dorsal root ganglion, the site in mammals where nociceptors reside, and limitations in the experimental tractability of these complicated organisms. The group of PIs submitting this proposal is expert in investigating the cellular mechanisms underlying sensory transduction in peripheral sensory neurons in Drosophila, rodents, and humans. The current proposal combines complementary expertise in a relevant rodent model of peripheral pain with an unbiased approach in a model organism to investigate the cellular and molecular mechanisms of CIPN. The goals of this proposal are to demonstrate that understanding gleaned from investigating the effects of CIPN-causing chemotherapy drugs on peripheral sensory neurons in a simple model organism can be used in a rational manner to direct more complicated studies in a relevant mammalian system in order to provide a powerful means for determining the cellular and molecular mechanism of CIPN and facilitate the discovery of new analgesics for the treatment of CIPN. Our preliminary results suggest the novel hypothesis that CIPN is a result of the direct effect of chemotherapy drugs on the sensory transduction machinery of peripheral nociceptors. We accomplish the goals of this R21 by testing three specific aims: Aim 1; to characterize a novel Drosophila model of CIPN that will be employed to direct experiments in relevant mammalian models of pain. Aim 2: To define the cellular and molecular mechanisms that underlie the effects of vinblastine and paclitaxel on sensory neuron function. And Aim 3: To investigate whether peripheral application of vinblastine and paclitaxel can induce CIPN in mammals. The importance and significance of the worked proposed here is supported by the recent funding announcement from the NIH/NCI: PA-12-083, "Biomechanisms of Peripheral Nerve Damage by Anti-Cancer Therapy (R21)". It is expected that the successful completion of the experiments described in this proposal will provide key understanding of fundamental mechanisms that underlie CIPN and establish a research team well-positioned to use rational and translational approaches to develop novel treatment strategies to counter CIPN.