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: 9791036
• 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/9791036
• 关键词: Adult; Alzheimer' s Disease; Area; Bos taurus structural-GP protein; 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; Stem cells; 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; glycoprotein structure; 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; 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）每年发生359,800事件。在CA的存活中，脑损伤是最大的 功能恢复的障碍。目前，药理学干预和治疗均未 体温过低会扭转CA造成的神经损伤。干细胞疗法在 脑损伤后神经元修复。但是，受伤部位的生存能力和整合不足，缺乏有效的效率 分化为所需的细胞类型阻碍了临床应用。 e 合并 代谢糖工程 （MGE）通过改性表面聚糖的技术影响细胞粘合剂和体外的分化，但是 在干细胞疗法的背景下尚未研究。因此，该提议的总体目的是 将MGE应用于基于细胞的疗法，以改善移植后细胞的粘合剂和活力 治疗效率可修复大约局部缺血大脑中受损的神经元的治疗效率。具体目的是： AIM1：借助我们新颖的MGE技术，我们假设一种基于聚糖的新干预能够 在体外促进人神经元干细胞（HNSC）神经元分化和细胞粘合剂。我们将发展和 优化具有较长烷基链，AC5Mannpropt和Ac5mannbutt的新型硫醇化甘露糖类似物， 预计会增加硫醇可及性并在体外促进HNSC细胞粘附和神经分化。 AIM2：通过优化的MANNAC类似物，我们假设处理过的HNSC将促进生存， 体内移植HNSC的分布和分化。我们将评估糖化的效果 HNSC关于CA后功能结果的HNSC并优化了基于细胞的治疗。 AIM 3：随着CA之后的预期结果提高，我们假设细胞的成功 基于干预是由于改善了移植糖化HNSC的生存和分化。我们 将在糖化HNSC移植后探索细胞相互作用和分子机制 通过Wnt/β-catenin信号通路CA。 意义在于MGE技术和干细胞疗法修复脑损伤的组合 CA后，基于细胞基于细胞的临床翻译的优化以及预期的发现 糖化NSC移植后生存和分化的基础机制。这 创新在于我们的创新假设，以通过MGE技术修改干细胞表面特性 改善细胞存活和分化，我们的新颖有效的MGE方法，其成本较低以修饰表面 HNSC的Glycans，以及我们在体内重要疾病中使用MGE技术来发展新型 基于治疗细胞的干预。我们的研究将导致新的治疗策略的发展 修复对未来临床干预措施的脑损伤，并最大程度地提高MGE和干细胞疗法的益处 基于新发现。糖模拟分子用于再生医学和干细胞疗法 将有助于改善基于细胞的治疗，以修复CA，中风和创伤引起的脑损伤或神经退行性 疾病，并具有巨大的潜力，可以提供深远的医疗进步。