Cellular Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

 描述(申请人提供)：化疗引起的周围神经病变(CIPN)和相关的疼痛是患者抗癌治疗的临床相关限制 毒品。目前，CIPN尚无有效的治疗方法。外周感觉神经元兴奋性的增强被认为与CIPN的发生和发展有关。通过直接影响膜的兴奋性，CIPN引起的化疗药物可能会增强神经元的活性，最终导致神经兴奋毒性和神经病变。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。到目前为止，很少有关于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。在哺乳动物身上进行这样的实验是复杂的，因为背根神经节中感觉神经元的异质性，哺乳动物伤害性感受器所在的位置，以及这些复杂生物在实验可控性方面的局限性。提交这项建议的PI小组是研究果蝇、啮齿动物和人类外周感觉神经元潜在的感觉转导的细胞机制方面的专家。目前的方案结合了相关啮齿动物外周疼痛模型中的互补专业知识和模型生物中的无偏见方法，以研究CIPN的细胞和分子机制。这一建议的目的是证明在一个简单的模式生物中通过研究引起CIPN的化疗药物对周围感觉神经元的影响而获得的理解可以合理地用于指导在相关哺乳动物系统中更复杂的研究，以便为确定CIPN的细胞和分子机制提供有力的手段，并促进发现治疗CIPN的新的止痛药。我们的初步结果表明，CIPN是化疗药物对外周伤害性感受器感觉转导机制直接作用的结果。我们通过测试三个特定目标来实现R21的目标：目标1；描述一种新的果蝇CIPN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：明确长春花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：探讨外周应用长春花碱和紫杉醇能否诱导哺乳动物CIPN。NIH/NCI：PA-12-083最近宣布的“抗癌治疗周围神经损伤的生物力学(R21)”支持了在此建议的工作的重要性和意义。预计本提案中描述的实验的成功完成将提供对CIPN基本机制的关键了解，并建立一支处于有利地位的研究团队，以使用合理和转换的方法来开发新的治疗策略来对抗CIPN。

 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.