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Stem Cell Surface Modification to Promote Nerve Regeneration

干细胞表面修饰促进神经再生

基本信息

批准号：
10543158
负责人：
Xiaofeng Jia
金额：
$ 43万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543158
关键词：
Address Adhesions Autologous Autologous Transplantation Cell Adhesion Cell Differentiation process Cell Survival Cell Therapy Cell Transplantation Cell surface Cell-Cell Adhesion Cells Chronic Clinical Clinical Research Data Derivation procedure Development Distal Dose Electric Stimulation Electrophysiology (science)Environment Extracellular Matrix Foundations Future Glycoengineering Growth Factor Harvest Human Impairment In Vitro Injury Intervention Metabolic Methodology Methods Modification Morbidity - disease rate Myopathy Natural regeneration Nature Nerve Nerve Regeneration Neurons Operative Surgical Procedures Oral Outcome Pathway interactions Patients Peripheral Nerves Peripheral nerve injury Polysaccharides Procedures Proliferating Property Protocols documentation Quality of life Recovery of Function Regenerative Medicine Regulation Safety Series Signal Pathway Source Stem cell transplant Sulfhydryl Compounds Surface Surface Properties Surgical incisions Techniques Technology Testing Time Tissues Transplantation Trauma Work adipose derived stem cell analog cell type clinical application cost efficacy evaluation functional outcomes improved improved outcome in vitro Assay in vivo in vivo evaluation innovation migration nerve gap nerve injury nerve repair nerve stem cell novel novel strategies novel therapeutic intervention peripheral nerve regeneration peripheral nerve repair repair model repaired sciatic nerve stem cell therapy stem cells success sugar supportive environment treatment optimization

项目摘要

Project Summary Peripheral nerve injury, especially critical-sized nerve gap injury, often results in poor recovery of function and impaired quality of life for the patient. Stem cell therapy holds significant promise; however, its clinical application has been largely hampered by limited stem cell adhesion and the lack of efficient differentiation. We have shown that our stem cell surface modification technique is able to profoundly influence specific cell-cell and cell-matrix interactions. Therefore, our specific aims are to develop and optimize novel candidate analogs to promote human adipose stem cell (hASC) adhesion and differentiation in vitro; to incorporate the cell surface modification technique into hASC-based therapies to improve peripheral nerve regeneration; and to investigate related mechanisms underlying improved nerve regeneration. Aim1: To develop and optimize novel analogs by metabolic glycoengineering (MGE) technology to promote hASC's cell adhesion and cell differentiation in vitro. We will optimize the cell surface modification with thiolated sugar analogs (ManNAc), evaluate the effects, and thoroughly characterize them to promote hASCs adhesion, proliferation, and differentiation. Aim2: To incorporate MGE into hASC-based therapies to improve peripheral nerve regeneration. With optimized ManNAc analogs, we will systemically evaluate the effect of glycoengineered hASCs on nerve regeneration after nerve repair and further optimize the therapy. Aim 3: To examine the mechanism by which thiol-derivatized ManNAc analogs contribute to nerve regeneration . With expected improvements in nerve regeneration, we will evaluate signaling pathways (e.g., Wnt / β after MGE'ed hASC transplantation. -catenin) modulated by MGE The innovation lies in our hypothesis to modify stem cell surface glycan properties with sugar analogs to improve cell survival and differentiation, our novel and effective technology, and the new application of these technologies in a fully translational nerve repair model to develop a novel treatment. The significance lies in the novel cell-based therapy with surface modification to address one of the most challenging aspects of nerve regeneration for critical-sized nerve gap repair, and the expected discovery of the mechanism underlying improved survival and differentiation by transplanted MGE'ed hASC. Our technology and protocols are highly translatable to the clinical environment. Success in this project will have direct translational implications for patients with peripheral nerve trauma requiring surgical repair. The clinical study of ManNAc has demonstrated the safety of single oral doses up to 6 g, and the FDA has approved the use of ManNAc to treat GNE Myopathy. Our study will lead to the development of novel therapeutic strategies for nerve repair that can contribute to future clinical interventions and maximize the benefits of stem cell therapy based on the new findings.

项目概要周围神经损伤，尤其是临界大小的神经间隙损伤，往往导致功能恢复不良和患者的生活质量受损。干细胞疗法具有重大前景；但其临床应用有限的干细胞粘附和缺乏有效的分化在很大程度上阻碍了这一过程。我们已经展示了我们的干细胞表面修饰技术能够深刻影响特定的细胞-细胞和细胞-基质互动。因此，我们的具体目标是开发和优化新的候选类似物，以促进人类脂肪干细胞（hASC）体外粘附和分化；纳入细胞表面修饰技术应用于基于 hASC 的疗法，以改善周围神经再生；并调查相关改善神经再生的机制。目标1：通过代谢糖工程（MGE）技术开发和优化新型类似物在体外促进hASC的细胞粘附和细胞分化。我们将优化细胞表面修饰硫醇化糖类似物 (ManNAc)，评估效果并彻底表征它们促进 hASC 的作用粘附、增殖和分化。目标 2：将 MGE 纳入基于 hASC 的疗法中，以改善周围神经再生。和优化的ManNAc类似物，我们将系统评估糖工程化的hASC对神经的影响神经修复后的再生并进一步优化治疗。目标 3：检查硫醇衍生的 ManNAc 类似物对神经的作用机制再生。随着神经再生的预期改善，我们将评估信号通路（例如，Wnt / MGE 处理的 hASC 移植后的β。 -连环蛋白）由 MGE 调节创新在于我们的假设，即用糖类似物改变干细胞表面聚糖的特性提高细胞存活和分化，我们新颖有效的技术，以及这些的新应用完全转化神经修复模型中的技术来开发一种新的治疗方法。其意义在于具有表面修饰的新型细胞疗法，可解决神经最具挑战性的方面之一临界大小神经间隙修复的再生，以及潜在机制的预期发现通过移植 MGE 处理的 hASC 提高了存活率和分化能力。我们的技术和协议非常可转化为临床环境。该项目的成功将对以下领域产生直接的转化影响：周围神经损伤需要手术修复的患者。 ManNAc 的临床研究表明单次口服剂量高达 6 g 的安全性，FDA 已批准使用 ManNAc 治疗 GNE 肌病。我们的研究将导致神经修复新治疗策略的开发，这有助于未来的临床干预措施，并根据新发现最大限度地发挥干细胞治疗的益处。