Molecular Mechanisms of Chemotherapy-Induced Cognitive Dysfunction

项目总结/摘要 认知功能障碍（“chemobrain”）是癌症化疗的重要不良后果， NCI认为这是一个认识不足的问题，目前的管理或 治疗策略有限或无效。我们的初步数据显示神经元ryanodine 内质网（ER）上的受体/钙释放通道（RyR 2）在细胞凋亡中被氧化和“泄漏”。 用阿霉素或甲氨蝶呤加5-FU治疗的小鼠。这些小鼠表现出认知功能障碍， 使用co-PI开发的新型口服小分子药物（Rycal，S107）进行改进， RyR 2通道泄漏。本申请的目的是：（1）建立和表征小鼠模型， 晚期人类乳腺癌，可用于研究细胞内钙（Ca 2+）是否通过 ER上的氧化神经元RyR 2是癌症化疗诱导的新机制。 神经认知功能障碍;和（2）测试修复渗漏的神经元RyR 2的新药Rycal（S107）是否 体内的通道可以防止化学毒素。拟议的研究将具有重要的临床意义，因为 Rycal S107与两种密切相关的Rycal属于同一化学类别，目前正在进行临床试验， 心脏和肌肉疾病，迄今为止，两者都具有良好的安全性。S107的优点是， 在大脑中的浓度超过10倍。（尽管S107由哥伦比亚大学申请专利，US 8，710，045， 2014年4月29日，所有研究者均可获得该药物，申请人未从其销售中获得任何收益）。这 初步数据表明，常用的化疗药物会引起认知障碍， 使用Rycal S107可以预防C57 BL 6小鼠的功能障碍，我们发表的数据显示， 渗漏的神经元RyR 2通道可导致应激诱导的认知功能障碍（创伤后应激 疾病，PTSD），其可以通过用S107口服治疗来改善。此应用程序旨在使 chemobrain和PTSD之间的新机制联系-细胞内Ca 2+泄漏-并测试潜在的 一种新的治疗方法，可以防止这种泄漏，并防止化疗。研究专家穆罕默德博士将 建立了有和没有乳腺癌的小鼠模型，并建立了认知功能障碍的存在， 这些模型通过测试几种化疗药物。穆罕默德医生将进行必要的 与其他团队成员进行实验，提供监督和培训支持，以保持高水平的 项目成功所需的研究一致性和生产力。

Project Summary/Abstract Cognitive dysfunction (“chemobrain”) is an important adverse sequel of cancer chemotherapy, the study of which has been identified by the NCI as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Our preliminary data show that neuronal ryanodine receptor/calcium release channels (RyR2) on the endoplasmic reticulum (ER) become oxidized and “leaky” in mice treated with doxorubicin or methotrexate plus 5-FU. These mice exhibit cognitive dysfunction that can be improved using a novel orally available small molecule drug (Rycal, S107) developed by the co-PI that fixes leaky RyR2 channels. The goals of this application are to: (1) establish and characterize a murine model of advanced human breast cancer that can be used to study whether intracellular calcium (Ca2+) leak via oxidized neuronal RyR2 on the ER is a novel mechanism underlying cancer chemotherapy-induced neurocognitive dysfunction; and (2) test whether the novel drug Rycal (S107) that fixes leaky neuronal RyR2 channels in vivo can prevent chemobrain. The proposed studies will have important clinical relevance as the Rycal S107 is in the same chemical class as two closely related Rycals that are currently in clinical testing for heart and muscle disorders, and to date both have excellent safety profiles. S107 has the advantage that it is concentrated >10-fold in the brain. (Although S107 is patented by Columbia University, US 8,710,045, 04/29/14, the drug is available to all investigators and the applicant receives no proceeds from its sale). This application is bolstered by preliminary data showing that commonly used chemotherapeutics cause cognitive dysfunction in C57BL6 mice that can be prevented using the Rycal S107, and by our published data showing that leaky neuronal RyR2 channels can cause stress-induced cognitive dysfunction (post-traumatic stress disorder, PTSD) that can be ameliorated by oral treatment with S107. This application aims to make the novel mechanistic link between chemobrain and PTSD - intracellular Ca2+ leak - and to test a potential novel therapy that prevents this leak and prevents chemobrain. Research specialist, Dr. Mohammad, will set up mouse models, with and without breast cancer, and establish the presence of cognitive dysfunction in those models by testing several chemotherapeutic agents. Dr. Mohammad will perform the necessary experiments with other team members, providing supervision and training support to maintain the high level of research consistency and productivity required for project success.