Stem cell transplantation therapy via intranasal delivery after stroke

中风后鼻内输送干细胞移植治疗

• 批准号: 9104350
• 负责人: LING WEI
• 金额: $ 34.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104350
• 关键词: Address; Adult; Animal Model; Animals; Attention; Autologous; Autologous Transplantation; Biological Neural Networks; Blood - brain barrier anatomy; Brain; Bypass; CXCR4 Receptors; CXCR4 gene; Cell Culture Techniques; Cell Survival; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Central Nervous System Diseases; Cerebral Ischemia; Chemotactic Factors; Clinical; Clinical Treatment; Clinical Trials; Electrophysiology (science); Environment; Ethics; Face; Gene Expression Regulation; Gene-Modified; Generations; Genomics; Goals; Health; Home environment; Homing; Human; Hypoxia; In Vitro; Intranasal Administration; Investigation; Ischemia; Ischemic Stroke; Lead; Lesion; Life; Mediating; Methods; Modeling; Molecular; Mus; Natural regeneration; Neuroglia; Neuronal Differentiation; Neurons; PTK2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Recovery of Function; Research; Rest; Risk; Route; Signal Transduction; Site; Somatic Cell; Stem Cell Research; Stem cell transplant; Stem cells; Stroke; Stromal Cell-Derived Factor 1; Techniques; Testing; Therapeutic; Therapeutic Effect; Transplantation; Viral Vector; Virus; barrel cortex; base; behavior test; brain tissue; cell motility; cell type; clinical application; effective therapy; expectation; experience; improved; in vivo; induced pluripotent stem cell; migration; mouse model; nerve stem cell; novel; novel strategies; optical imaging; post stroke; preconditioning; public health relevance; regenerative; regenerative therapy; repaired; research study; restoration; stem; stem cell therapy; stroke therapy; stroke treatment; synaptogenesis; tissue repair; tumor; tumor growth; vector

 DESCRIPTION (provided by applicant): Stem cell transplantation offers a promising regenerative therapy for cerebral ischemia and other CNS disorders. Of the several cell types for cell-based therapeutics, induced pluripotent stem (iPS) cells have received a great deal of attention due to their ability to develop into neurons and non-neuronal cells, the possibility of autologous transplantation and the lack of ethical controversies. These cells created by viral vectors of genomic integration, unfortunately, have a potential risk of tumor growth. In addition, current methods of cell delivery are either invasive or inefficient; transplanted cells suffer from poor cell survival in the host ischemic brain and insufficient homing to the lesion site. Based on our recent progress in stroke therapy using stem cells and neural progenitor cells (NPCs) and the experience in intranasal drug/trophic factor delivery, we now propose to test intranasal delivery of virus-free human iPS-NPCs pretreated with hypoxic preconditioning (HP) as a non-invasive and brain specific transplantation method for enhanced therapeutic benefits after focal ischemic stroke. Specific Aim 1 will examine the promoting effect of HP strategy and CXCR-4 expression in human iPS-NPCs on directed cell migration in vitro. Gene regulation and differentiation of HP-treated, CXCR-4 and/or FAK expressing cells will be examined. Specific Aim 2 will test the therapeutic effects of the strategies in Aim 1 in our unique barrel cortex stroe model of mice, with the expectation of improved survival, differentiation, and enhanced homing of iPS- NPCs to the ischemic cortex after intranasal delivery. Specific Aim 3 will examine neural network repair and functional recovery after the iPS-NPC therapy for restoration of the intracortical and thalamocortical connections and sensorimotor activity after the focal ischemic damage. This investigation takes advantage of the complementary expertise in our collaborative team and is based on recently developed novel strategies in stem cell research and stroke therapy. Our ultimate goal is to develop a non-invasive yet highly effective and more efficient cell-based therapy for clinical treatment of ischemic stroke.

 描述（由适用提供）：干细胞移植为脑缺血和其他中枢神经系统疾病提供了承诺的再生疗法。在基于细胞治疗的几种细胞类型中，诱导多能茎（IPS）细胞由于能够发展为神经元和非神经元细胞的能力，自体移植的可能性以及缺乏伦理争议的可能性，因此受到了很大的关注。不幸的是，这些由基因组整合的病毒载体产生的细胞具有潜在的肿瘤生长风险。另外，当前的细胞输送方法要么是侵入性或效率低下的方法。移植的细胞患有 宿主缺血性脑的细胞存活不良，病变部位的归巢不足。根据我们使用干细胞和神经元素细胞（NPC）（NPC）的最新进展以及鼻内药物/营养因子递送的经验，我们现在提议测试通过鼻内递送无病的人IPS-NPC，以通过非侵入性和脑部特定的促进性促进性促进性促进培养在于，以促进性促进性促进性促进性促进性促进性促进性促进性较高的培养基培养基培养基的促进性促进性促进性促进性促进型培训方法HP策略和CXCR-4在人IPS-NPC中表达对定向细胞迁移的影响。 HP处理，CXCR-4和/或FAK表达细胞的基因调节和分化。特定的目标2将在我们独特的小鼠桶皮层模型中测试AIM 1中这些策略的治疗作用，并期望在鼻腔内递送后提高生存率，分化和增强IPS-NPC对缺血性皮质的归巢。特定的目标3将检查IPS-NPC治疗后的神经元网络修复和功能恢复，以恢复局灶性缺血性损伤后的心脏内和丘脑皮层连接以及感觉运动活性。这项投资利用了我们合作团队中的完整专业知识，并基于最近开发的干细胞研究和中风疗法的新型策略。我们的最终目标是开发一种非侵入性但高效，更有效的基于细胞的治疗，用于缺血性中风的临床治疗。