Mesenchymal Stem Cells to Repair Chemobrain

项目概要 化疗引起的认知缺陷（“化疗脑”）是癌症治疗的一个主要副作用， 通常会持续很长时间直到生存。目前尚无 FDA 批准的药物用于预防或治疗化疗 mobrain 及其潜在机制知之甚少。该应用程序旨在填补这一空白 回答了挑衅性问题#9：什么是分子和/或细胞机制？ 癌症治疗引起的严重不良后遗症的发展是什么？ 我们之前在缺血性脑损伤模型中的工作表明，经鼻应用间充质 干细胞迁移到大脑中，通过促进内源性恢复认知和感觉运动功能障碍 修复机制导致大脑结构恢复并抑制神经炎症。我们的 初步数据表明，顺铂会诱导小鼠认知缺陷，这与认知能力下降有关 神经发生、白质组织和树突棘完整性异常以及线粒体受损 软骨呼吸。初步数据表明，鼻内给药的间充质干细胞（MSC） 进入大脑，恢复认知缺陷并使线粒体功能正常化。初步体外实验 数据表明，MSC 将健康的线粒体转移到顺铂损伤的神经元中。 我们的工作假设是，顺铂通过引起持续的线粒体功能障碍来诱发认知缺陷。 损伤导致神经炎症、干细胞耗竭、白质组织异常和 树突棘完整性和突触连接受损。我们建议鼻腔给予 MSC 重新 通过恢复线粒体功能和抑制神经炎症来对抗 CICI。为了检验我们的假设，我们 将追求以下具体目标： 目标 1：通过鼻内施用 MSC 治疗 CICI；目标 2： 确定经鼻给药的间充质干细胞是否迁移到大脑中以促进内源性修复机制 尼主义；目标 3：确定顺铂和 MSC 对大脑影响的机制。 这项研究具有创新性，因为：a) 我们将是第一个全面分析小鼠神经元 CICI 的研究。 衰老、细胞、线粒体和炎症水平； b) 通过鼻腔给药恢复 CICI 的潜力 MSC 尚未测试； c) MSC 将线粒体转移到体内受损神经元的假设 尚未经过测试； c) 成功完成这项研究将确定潜在的关键分子机制 化学脑； d) 我们将提供化学脑可以修复的原理证明。 这个项目意义重大，因为化疗脑是癌症治疗的常见副作用，通常会导致 坚持生存并降低生活质量。我们已经在小鼠身上进行了广泛的安全性研究 MSC 治疗缺血性脑损伤。该项目的成功完成将迈出第一步 旨在治疗化疗引起的脑损伤和相关功能障碍 神经系统外的莫里斯或其他癌症治疗，包括脑肿瘤的放射治疗。

PROJECT SUMMARY Chemotherapy-induced cognitive deficit (“chemobrain”) is a major side effect of cancer treatment that fre- quently persists long into survivorship. There are no FDA-approved drugs for prevention or treatment of che- mobrain, and the underlying mechanisms are poorly understood. This application aims at filling this void and responds to provocative question #9: What are the molecular and/or cellular mechanisms that un- derlie the development of cancer therapy-induced severe adverse sequelae? Our previous work in models of ischemic brain damage demonstrated that nasally applied mesenchymal stem cells migrate into the brain to restore cognitive and sensorimotor dysfunction, by promoting endogenous repair mechanisms leading to restoration of brain structure and by suppression of neuro-inflammation. Our preliminary data show that cisplatin induces cognitive deficits in mice that are associated with decreased neurogenesis, abnormalities in white matter organization and dendritic spine integrity, and impaired mito- chondrial respiration. Preliminary data indicate that mesenchymal stem cells (MSC) administered intranasally travel into the brain, restore the cognitive deficits and normalize mitochondrial function. Preliminary in vitro data indicates that MSC transfer healthy mitochondria to neurons damaged by cisplatin. Our working hypothesis is that cisplatin induces cognitive deficits by causing persistent mitochondrial damage leading to neuroinflammation, stem cell depletion, abnormalities in white matter organization and dendritic spine integrity, and impaired synaptic connectivity. We propose that nasally administered MSC re- verse CICI by restoring mitochondrial function and suppressing neuroinflammation. To test our hypothesis we will pursue the following Specific Aims: Aim 1: Treat CICI by intranasal administration of MSCs; Aim 2: Determine whether nasally administered MSCs migrate into the brain to promote endogenous repair mecha- nisms; and Aim 3: Determine the mechanisms underlying the effect of cisplatin and MSC on the brain. This study is innovative because: a) we will be the first to fully analyze CICI in the mouse at the neuroim- aging, cellular, mitochondrial and inflammatory levels; b) the potential to restore CICI by nasal administration of MSC has not been tested; c) the hypothesis that MSC transfer mitochondrial to damaged neurons in vivo has not been tested; c) successful completion of this study will identify key molecular mechanisms underlying chemobrain; and d) we will provide proof of principle that chemobrain can be repaired. This project is significant because chemobrain is a common side effect of cancer treatment that often per- sists into survivorship and reduces quality of life. We have already performed extensive safety studies in mice treated with MSC for ischemic brain damage. Successful completion of this project will provide the first step toward a treatment for brain damage and associated functional impairments caused by chemotherapy for tu- mors outside the nervous system or by other cancer treatments, including radiation therapy for brain tumors.