Mesenchymal Stem Cells to Repair Chemobrain

间充质干细胞修复化疗脑

• 批准号: 9547805
• 负责人: Cobi J Heijnen
• 金额: $ 40.21万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9547805
• 关键词: Address; Adverse effects; Adverse event; Aging; Area; Behavioral; Brain; Brain Injuries; Brain Neoplasms; Brain region; Bromodeoxyuridine; Cancer Patient; Cell Proliferation; Cells; Chemotactic Factors; Cisplatin; Clinical Research; Cognitive; Cognitive deficits; Data; Dendritic Spines; Development; Diagnosis; Differentiation and Growth; Dose; Dyes; Electron Microscopy; FDA approved; Fiber; Functional disorder; Genus Hippocampus; Golgi Apparatus; Growth Factor; Immunofluorescence Immunologic; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammatory; Intervention; Intranasal Administration; Ischemic Brain Injury; Knowledge; Label; Magnetic Resonance Imaging; Mediating; Mesenchymal Stem Cells; Methodology; Mitochondria; Modeling; Molecular; Morphology; Mus; Myelin Basic Proteins; Nervous system structure; Neuroglia; Neurons; Neuropsychology; Nose; Patients; Performance; Pharmaceutical Preparations; Platinum; Polymerase Chain Reaction; Prevention; Preventive; Quality of life; Questionnaires; Radiation therapy; Research; Respiration; Rodent Model; Schedule; Social Discrimination; Solid Neoplasm; Stains; Stem cells; Structural defect; Structure; Synapses; Techniques; Testing; Time; Travel; Vertebral column; Work; base; cancer therapy; chemobrain; chemotherapy; cognitive function; connectome; density; fluorescence imaging; functional disability; in vivo; innovation; mRNA Expression; mouse model; nerve stem cell; neurogenesis; neuroimaging; neuroinflammation; neurotoxic; novel; patient subsets; preclinical study; repaired; restoration; safety study; stem cell therapy; survivorship; white matter; white matter damage

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.

项目总结 化疗所致的认知障碍是癌症治疗的一个主要副作用。 坚定不移地活了很久。目前还没有FDA批准的药物来预防或治疗CHE- 运动脑，其潜在机制还知之甚少。本申请旨在填补这一空白，并 回答了挑衅性的问题#9：什么是分子和/或细胞机制 德利癌症治疗的发展引发严重的不良后遗症？ 我们先前在缺血性脑损伤模型中的工作表明，鼻腔应用间充质 干细胞通过促进内源性激素进入大脑，修复认知和感觉运动功能障碍 修复机制导致大脑结构的恢复和抑制神经炎症。我们的 初步数据显示，顺铂可导致小鼠认知缺陷，这种缺陷与认知功能减退有关 神经发生，白质组织和树突棘完整性异常，以及有丝分裂障碍- 软骨呼吸。初步数据显示，间充质干细胞(MSC)鼻腔内注射 进入大脑，恢复认知缺陷，使线粒体功能正常化。初步的体外实验 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性线粒体而导致认知障碍。 损伤导致神经炎症、干细胞耗竭、白质组织异常和 树突棘的完整性，以及突触连接受损。我们建议鼻腔给药的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：通过鼻内注射间充质干细胞治疗CiCi；目标2： 确定鼻腔注射的MSCs是否迁移到脑内促进内源性修复机制- 目标3：确定顺铂和MSC对大脑影响的潜在机制。 这项研究具有创新性，因为：a)我们将是第一个在小鼠的神经肌层全面分析CiCi的人。 衰老、细胞、线粒体和炎症水平；b)通过鼻腔给药恢复CiCi的可能性 C)MSC将线粒体转移到体内受损神经元的假说 尚未经过测试；c)这项研究的成功完成将确定 化学反应；和d)我们将提供化学反应可以修复的原则证据。 这个项目意义重大，因为化疗是癌症治疗的常见副作用，通常是 坚持生存，降低生活质量。我们已经在老鼠身上进行了广泛的安全性研究。 骨髓间充质干细胞治疗缺血性脑损伤。该项目的成功完成将提供第一步 寻找治疗肿瘤化疗所致脑损伤及相关功能障碍的方法 神经系统外的MORS或通过其他癌症治疗，包括脑瘤的放射治疗。