Targeting Neural Mitochondria to Treat Chemotherapy-Induced Peripheral Neuropathy

描述（由申请方提供）：化疗诱导的周围神经病变（CIPN）是使用常用药物（如紫杉烷类和铂类化合物）治疗癌症的患者中剂量减少或治疗中止的最常见原因。患有CIPN的患者报告外周感觉敏感性丧失、刺痛和疼痛单独或组合地呈“长袜和手套”分布。随着蛋白酶体抑制剂和靶向治疗等新药的出现，这种毒性的发生率预计会增加。最近的估计表明，每年有数十万患者患有CIPN，这种毒性的剂量限制效应可能会影响生存率。此外，周围神经病变对生活质量有重大影响。目前还没有FDA批准的CIPN治疗方法，其潜在机制才刚刚开始被理解。啮齿动物研究表明CIPN的病理生理学中存在神经线粒体损伤。我们已经表明，在缺血性脑损伤模型中，抑制促凋亡因子p53的积累或抑制应激激酶c-Jun N-末端激酶（JNK）的活化特异性地在线粒体处保护脑神经元线粒体的完整性并减少神经元损失。在这里，我们建议将这些知识应用于预防CIPN。我们的工作假设是，JNK激活或p53积累在外周神经元线粒体的局部靶向将防止CIPN的发展。为了验证我们的假设，我们将追求以下三个具体目标：1：确定线粒体JNK/P53的局部靶向对紫杉醇诱导的机械性痛觉过敏的作用，并验证其不干扰癌症治疗; 2：抑制JNK/P53通路以防止感觉运动功能障碍和爪神经支配的丧失; 3：研究有助于局部治疗保护作用的细胞生物学机制。这项研究应用是创新的，因为：（a）外周神经元中的线粒体P53/JNK通路尚未被靶向以保护免受化疗诱导的神经元损伤和周围神经病变;这种新的靶点可能为预防CIPN开辟一系列新的治疗手段。(b)这项研究的成功完成不仅将开辟新的治疗选择，但也提供了行为测试评估啮齿动物的感觉运动缺陷。这些测试将允许回答的问题是否相同或不同的分子机制的基础疼痛和感觉运动缺陷的特征CIPN。(c)到目前为止，治疗CIPN的啮齿动物研究大多忽略了对癌症治疗的潜在干扰。我们计划使用p53阳性和阴性肿瘤分析体内和体外药物治疗的潜在干扰。该项目意义重大，因为它可能导致开发新的干预措施来预防CIPN，CIPN仍然是癌症治疗患者的主要剂量限制性毒性。线粒体损伤也可能是周围糖尿病神经病变的起源，并导致其他形式的神经性疼痛，因此预期的发现也应该使这一大群患者受益。

DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequent cause of dose reduction or treatment discontinuation in patients treated for cancer with commonly used drugs such as taxanes and platinum-based compounds. Patients with CIPN report loss of peripheral sensory sensitivity, tingling, and pain separately or in combination in a 'stocking and glove' distribution. The incidence of this toxicity is anticipated t increase as newer drugs like proteasome inhibitors and targeted therapies are also frequently leading to CIPN. Recent estimates indicate that several hundred thousand patients suffer from CIPN each year and the dose limiting effects of this toxicity are likely to impact survival. In addition, peripheral neuropathy has a major impact on quality of life. There are no FDA-approved treatments for CIPN and the underlying mechanisms are only begun to be understood. Rodent studies implicate neural mitochondrial damage in the pathophysiology of CIPN. We have shown that inhibition of the accumulation of the pro-apoptotic factor p53 or inhibition of activation of the stress kinase c-Jun N-terminal Kinase (JNK) specifically at the mitochondria protects cerebral neuronal mitochondrial integrity and reduces neuronal loss in a model of ischemic brain damage. Here we propose to apply this knowledge to the prevention of CIPN. Our working hypothesis is that local targeting of JNK activation or p53 accumulation at the mitochondria in peripheral neurons will prevent development of CIPN. To test our hypothesis we will pursue the following three specific aims: 1: Determine the effect of local targeting of mitochondrial JNK/P53 on paclitaxel-induced mechanical hyperalgesia and verify that it does not interfere with cancer therapy 2: Inhibit the JNK/p53 pathway to protect against sensorimotor dysfunction and loss of paw innervation; 3: Investigate the cell biological mechanisms contributing to the protective effects of local treatment. This research application is innovative because: (a) the mitochondrial P53/JNK pathway in peripheral neurons has not been targeted to protect against chemotherapy-induced neuronal damage and peripheral neuropathy; this novel target is likely to open up a new range of therapeutic means for preventing CIPN. (b) Successful completion of this study will not only open novel therapeutic options but also provide behavioral tests for assessing sensorimotor deficits in rodents. These tests will allow answering the question whether the same or distinct molecular mechanisms underlie pain and sensorimotor deficits that are characteristic of CIPN. (c) Until now, rodent studies treating CIPN mostly ignored potential interference with cancer therapy. We plan to analyze a potential interference of drug treatment in vivo as well as in vitro using p53 positive and negative tumors. This project is significant because it will likely lead to development of novel interventions for prevention of CIPN, still the major dose-limiting toxicity in patients treated for cancer. Mitochondrial damage i probably also at the origin of peripheral diabetic neuropathy and contributes to other forms of neuropathic pain, so the expected findings should benefit this large population of patients as well.