Mesenchymal Stem Cells to Repair Chemobrain

项目摘要 化疗引起的认知缺陷（“chemobrain”）是癌症治疗的主要副作用， 长期坚持到生存。没有FDA批准的药物用于预防或治疗慢性- Mobrain，其潜在机制尚不清楚。本申请旨在填补这一空白， 回答挑衅性的问题#9：什么是分子和/或细胞机制，联合国- Derlie癌症治疗引起的严重不良后遗症的发展？ 我们以前在缺血性脑损伤模型中的工作表明，鼻内应用间充质干细胞可以促进脑缺血。 干细胞迁移到大脑中，通过促进内源性神经元的功能恢复认知和感觉运动功能障碍， 修复机制导致脑结构的恢复和抑制神经炎症。我们 初步数据显示顺铂诱导小鼠的认知缺陷， 神经发生、白色组织和树突棘完整性异常以及线粒体受损， 呼吸困难。初步数据表明，间充质干细胞（MSC）鼻内给药 进入大脑，恢复认知缺陷并使线粒体功能正常化。初步体外 数据表明MSC将健康的线粒体转移到被顺铂损伤的神经元。 我们的工作假设是，顺铂通过引起持续的线粒体 损伤导致神经炎症、干细胞耗竭、白色组织异常， 树突棘完整性和受损的突触连接。我们建议鼻内给药的MSC重新- 通过恢复线粒体功能和抑制神经炎症来对抗CICI。为了验证我们的假设， 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MSC是否迁移到大脑中以促进内源性修复机制。 目的3：确定顺铂和MSC对脑作用的机制。 这项研究是创新的，因为：a）我们将是第一个在小鼠的神经组织中全面分析CICI的人， 老化、细胞、线粒体和炎症水平; B）通过鼻施用恢复CICI的潜力 c）MSC在体内将线粒体转移到受损神经元的假设 c）成功完成这项研究将确定关键的分子机制， chemobrain;和d）我们将提供chemobrain可以修复的原理证明。 这个项目是重要的，因为chemobrain是癌症治疗的常见副作用，通常是 影响生存率并降低生活质量。我们已经在小鼠身上进行了广泛的安全性研究 治疗缺血性脑损伤该项目的成功完成将提供第一步 用于治疗由肿瘤化疗引起的脑损伤和相关功能障碍， 神经系统外的mors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.