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: 10201773
• 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/10201773
• 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; efficacy evaluation; functional outcomes; improved; in vivo; in vivo Model; innovation; migration; natural hypothermia; nerve injury; nerve stem cell; novel; novel strategies; novel therapeutic intervention; 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.

项目概要 每年心脏骤停 (CA) 的发生率为 359,800 例。 CA幸存者中，脑损伤最为严重 妨碍功能恢复。目前，无论是药物干预还是治疗 低温可以逆转CA引起的神经损伤。干细胞疗法在以下领域具有重大前景 脑损伤后的神经元修复。然而，受伤部位的生存能力和整合能力较差，并且缺乏有效的治疗方法。 分化成所需的细胞类型阻碍了临床应用。乙 合并 代谢糖工程 （MGE）技术通过修饰表面聚糖影响体外细胞粘附和分化，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 应用于基于细胞的疗法，以改善移植后的细胞粘附和活力，并增强 CA后修复缺血脑损伤神经元的治疗效果。具体目标是： 目标 1：通过我们新颖的 MGE 技术，我们假设一种新颖的基于聚糖的干预措施能够 在体外促进人神经干细胞（hNSC）的神经分化和细胞粘附。我们将开发和 优化具有更长烷基链的新型硫醇化 ManNAc 类似物 Ac5ManNPropT 和 Ac5ManNButT，它们是 预计可增加硫醇可及性并促进体外 hNSC 细胞粘附和神经分化。 目标 2：通过优化的 ManNAc 类似物，我们假设经过处理的 hNSC 将促进存活， 移植hNSCs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疗法。 目标 3：随着 CA 后结果的预期改善，我们假设细胞的成功- 基于糖基工程的干预是由于移植的糖基化 hNSC 的存活和分化得到改善。我们 将探索糖工程 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。 意义在于MGE技术与干细胞疗法相结合修复脑损伤 CA后，基于细胞的治疗向临床转化的优化，以及预期的发现 糖工程 NSC 移植后生存和分化改善的机制。这 创新在于我们的创新假设是通过MGE技术改变干细胞表面特性 提高细胞存活和分化，我们新颖有效的 MGE 方法，表面修饰成本低 hNSC 的聚糖，以及我们在重要疾病体内模型中使用 MGE 技术开发新的聚糖 基于细胞的治疗干预。我们的研究将导致新的治疗策略的发展 修复脑损伤以适应未来的临床干预并最大限度地发挥 MGE 和干细胞治疗的益处 基于新的发现。糖类似物分子在再生医学和干细胞疗法中的应用 将有助于改善基于细胞的疗法，以修复因 CA、中风、创伤或神经退行性疾病引起的脑损伤 疾病，并具有提供深远的医学进步的巨大潜力。