Brain Recovery after Cardiac Arrest with Metabolic Glycoengineered Stem Cells

代谢糖工程干细胞促进心脏骤停后的大脑恢复

• 批准号: 9979983
• 负责人: Xiaofeng Jia
• 金额: $ 33.8万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979983
• 关键词: Adult; Alzheimer' s Disease; Area; Brain; Brain Injuries; Brain Ischemia; Carbohydrates; Cardiopulmonary Resuscitation; Cause of Death; Cell Adhesion; Cell Differentiation process; Cell Survival; Cell Therapy; Cell-Cell Adhesion; Cells; Clinical; Data; Development; Disease; Electrophysiology (science); Future; Glycocalyx; Goals; Heart Arrest; Histology; Homing; Hospitals; Human; Huntington Disease; In Vitro; Incidence; Induced Heart Arrest; Injury; Intervention; Investigation; Ischemia; Magnetic Resonance Imaging; Medical; Metabolic; Methods; Modeling; Modification; Molecular; Monosaccharides; Multiple Sclerosis; Neurodegenerative Disorders; Neurologic Deficit; Neurological outcome; Neuronal Differentiation; Neuronal Injury; Neurons; Outcome; Parkinson Disease; Pharmacology; Polysaccharides; Rattus; Recovery; Recovery of Function; Regenerative Medicine; Reperfusion Injury; Safety; Sialic Acids; Signal Pathway; Site; Stem cell transplant; Stroke; Sulfhydryl Compounds; Surface; Surface Properties; Survivors; Techniques; Technology; Therapeutic; Time; Translating; Transplantation; Trauma; Treatment Efficacy; analog; base; beta catenin; brain repair; cell type; clinical application; clinical translation; cost; functional outcomes; improved; in vivo; in vivo Model; innovation; migration; natural hypothermia; nerve injury; nerve stem cell; novel; novel strategies; novel therapeutics; out-of-hospital cardiac arrest; preclinical study; relating to nervous system; repaired; stem cell differentiation; stem cell therapy; stem cells; structural glycoprotein; success; sugar

Project Summary Cardiac arrest (CA) has an incidence of 359,800 annually. Among survivors of CA, brain injury is the biggest impediment to functional recovery. Currently, neither pharmacological intervention nor therapeutic hypothermia can reverse the neural injury caused by CA. Stem cell therapy holds significant promise in the neuronal repair after brain injury. However, poor viability and integration at the site of injury and lack of efficient differentiation into the desired cell types hinder clinical applications. E merging metabolic glycoengineering (MGE) technology by modification of surface glycans impacts cell adhesion and differentiation in vitro, however, has not been investigated in the context of stem cell therapy. Therefore, the overall aim of this proposal is to apply MGE to cell-based therapies to improve cell adhesion and viability after transplantation and enhance the treatment efficacy to repair damaged neurons in ischemia brain after CA. The specific aims are: Aim1: With our novel MGE technique, we hypothesize that a novel glycan-based intervention is able to promote human neural stem cell (hNSCs) neural differentiation and cell adhesion in vitro. We will develop and optimize novel thiolated ManNAc analogs with longer alkyl chains, Ac5ManNPropT and Ac5ManNButT, that are predicted to increase thiol accessibility and promote hNSCs cell adhesion and neural differentiation in vitro. Aim2: With optimized ManNAc analogs, we hypothesize that treated hNSCs will promote the survival, distribution, and differentiation of transplanted hNSCs in vivo. We will evaluate the effect of glycoengineered hNSCs on functional outcome after CA and optimize this cell-based therapy. Aim 3: With expected improvement in outcome after CA, we hypothesize that the success of the cell- based intervention is due to improved survival and differentiation of transplanted glycoengineered hNSCs. We will explore cellular interactions and molecular mechanisms after glycoengineered hNSC transplantation after CA through Wnt/β-catenin signaling pathways. The Significance lies in the combination of the MGE technique and stem cell therapy for repairing brain injury post-CA, optimization of cell-based therapy towards clinical translation, and the expected discovery of the mechanism underlying improved survival and differentiation after glycoengineered NSC transplantation. The innovation lies in our innovative hypothesis to modify stem cell surface properties by MGE technology to improve cell survival and differentiation, our novel and effective MGE method with low cost for modifying surface glycans of hNSCs, and our use of the MGE technique in important disease in vivo model to develop novel therapeutic cell-based intervention. Our study will lead to the development of novel therapeutic strategies to repair brain injury towards future clinical interventions and maximize the benefits of MGE and stem cell therapy based on the new findings. The use of sugar analog molecules for regenerative medicine and stem cell therapies will help improve cells based therapy to repair brain injury due to CA, stroke, and trauma, or neurodegenerative diseases, and have tremendous potential to provide a profound medical advance.

项目摘要 心脏骤停（CA）每年的发病率为359，800。在CA的幸存者中，脑损伤是最大的 阻碍功能恢复。目前，无论是药物干预还是治疗， 低温可逆转CA引起的神经损伤。干细胞治疗在世界范围内具有重要的前景。 脑损伤后的神经元修复。然而，在损伤部位的存活力和整合差以及缺乏有效的 分化成所需的细胞类型阻碍了临床应用。E 合并 代谢糖工程 (MGE)通过修饰表面聚糖的技术在体外影响细胞粘附和分化，然而， 尚未在干细胞治疗的背景下进行研究。因此，本提案的总体目标是 将MGE应用于基于细胞的治疗，以改善移植后的细胞粘附和存活力，并增强 CA后缺血脑损伤神经元修复的治疗效果。具体目标是： 目标1：通过我们的新型MGE技术，我们假设一种新型的基于聚糖的干预能够 促进人神经干细胞（hNSCs）的神经分化和细胞粘附。创新和 优化具有较长烷基链的新型硫醇化ManNAc类似物Ac 5 ManNPropT和Ac 5 ManNButT， 预测增加巯基可接近性并促进体外hNSC细胞粘附和神经分化。 目标2：使用优化的ManNAc类似物，我们假设处理的hNSC将促进存活， 移植的hNSC在体内的分布和分化。我们将评估糖工程的效果 hNSC对CA后功能结果的影响，并优化这种基于细胞的治疗。 目的3：随着CA后结局的预期改善，我们假设细胞的成功- 基于干预的结果是由于移植的糖工程化hNSC的存活和分化改善。我们 将探索糖工程化hNSC移植后的细胞相互作用和分子机制， CA通过Wnt/β-catenin信号通路。 MGE技术与干细胞治疗相结合对脑损伤修复的意义 后CA，优化基于细胞的治疗向临床转化，以及预期的发现， 糖工程化NSC移植后存活和分化改善的潜在机制。的 创新在于我们的创新假设，即通过MGE技术改变干细胞表面性质， 改善细胞存活和分化，我们新的和有效的低成本的MGE方法用于修饰表面 我们使用MGE技术在重要的疾病体内模型中开发了新的hNSC聚糖， 基于细胞的治疗性干预。我们的研究将导致新的治疗策略的发展， 修复脑损伤，以实现未来临床干预，并最大限度地发挥MGE和干细胞治疗的益处 根据新的发现。糖类似物分子在再生医学和干细胞治疗中的应用 将有助于改善基于细胞的治疗，以修复由于CA，中风和创伤或神经退行性疾病引起的脑损伤 疾病，并有巨大的潜力提供一个深刻的医学进步。