Scaffold-supported neural progenitor cell grafting to improve stroke recovery

支架支持的神经祖细胞移植可改善中风恢复

• 批准号: 8508013
• 负责人: Matthew Barry Jensen
• 金额: $ 19.11万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508013
• 关键词: Affect; Anatomy; Arteries; Astrocytosis; Award; Axon; Basic Science; Behavioral; Biological Models; Biological Response Modifier Therapy; Biology; Brain; Brain Injuries; Cell Differentiation process; Cell Survival; Cell Therapy; Cells; Clinical Research; Clinical Trials; Corpus striatum structure; Cultured Cells; Data; Development; Development Plans; Diffuse; Disabled Persons; Distant; Environment; Ethical Issues; Extracellular Matrix; Extramural Activities; Funding; Gel; Goals; Human; Immunosuppression; In Situ; In Vitro; Infarction; Inflammation; Injury; Internships; Ischemic Stroke; Knowledge; Label; Laboratories; Lead; Length; Liquid substance; Location; Mentors; Modeling; Molecular; Natural regeneration; Needles; Nervous system structure; Neural Pathways; Neuroglia; Neuronal Differentiation; Neurons; Neurosciences; Outcome; Patients; Physicians; Public Health; Rattus; Recovery; Recovery of Function; Relative (related person); Research; Research Project Grants; Science; Scientist; Somatosensory Cortex; Stem cells; Stroke; Structure; Survivors; Synapses; System; Testing; Thalamic structure; Therapeutic; Tissue Grafts; Tissues; Training; Translating; Translational Research; Transplantation; Transplanted tissue; angiogenesis; blastomere structure; brain tissue; career development; disability; effective therapy; fetus cell; improved; in vivo; induced pluripotent stem cell; injured; innovation; nerve stem cell; neuronal replacement; post stroke; public health relevance; reconstitution; relating to nervous system; repaired; response; responsible research conduct; scaffold; somatosensory; stroke recovery; synaptogenesis; thalamocortical tract; translational study

DESCRIPTION (provided by applicant): My long-term goal is to improve the recovery of stroke patients through basic and translational research of biological therapies like neural cell grafting. Because my background is in clinical research, my goal for the K08 award is to get the intensive basic science training and mentored research I need to build an R01-funded independent basic science lab that will lead to later translational studies of these exciting potential treatments. Research project: Post-stroke disability is a major public health problem. Intracerebral grafting of human neural progenitor cells is a promising potential therapy to improve recovery after stroke. Translating this treatment from the laboratory to clinical trials is challenged by the unfavorable environment for graft cell survival caused by structural disruption of brain tissue. Numerous materials termed scaffolds are available to provide structural support for graft cells, but few comparison data are available for selection. In Aim 1, we will test the hypothesis that scaffolds with different molecular compositions may affect the survival or neural differentiation of human induced pluripotent cells in vitro. This data will allow better scaffold selection for subsequent grafting studies. Infarcted host tissue responses, including inflammation, astrocytosis, and angiogenesis, may also affect the fate of graft cells and scaffolds. Additionally, these graft-scaffold-host interactions may vary depending on the distance from the infarct. In Aim 2, we will test the hypothesis that graft cells, scaffolds, and hst tissue respond to each other in spatially-dynamic ways that are important for graft and tissue outcomes in a rat lacunar stroke model. The therapeutic potential of graft-host neuronal synapses reconnecting an infarcted neural pathway may also be influenced by the grafting location relative to the damaged tract. A small, targeted infarct of the somatosensory thalamocortical tract, which occurs with the human stroke type termed thalamic lacune, provides an ideal model system to evaluate the effects of graft placements on tract reconnection. In Aim 3, we will test the hypothesis that graft location will influence functional recovery of a rat mode of thalamic lacunar stroke through graft-host connectivity. Career development plan: My primary mentor will be stem cell neuroscientist Su-Chun Zhang, who will oversee the stem cell and neuroscience aspects of my research as well as my overall career development. I will also have one co-mentor each to focus specifically on the stroke science, the K08 physician-scientist aspects of my training, and my overall career development and training in the responsible conduct of research. I will supplement hands-on basic science training from mentors and consultants with coursework and extramural lab internships from leaders in the fields of cell therapy and brain injury recovery.

描述（由申请人提供）：我的长期目标是通过神经细胞移植等生物疗法的基础和转化研究来改善中风患者的康复。因为我的背景是临床研究，所以我获得 K08 奖的目标是获得所需的强化基础科学培训和指导研究，以建立一个由 R01 资助的独立基础科学实验室，该实验室将导致这些令人兴奋的潜在治疗方法的后续转化研究。研究项目：中风后残疾是一个重大的公共卫生问题。人类神经祖细胞的脑内移植是改善中风后恢复的一种有前途的潜在疗法。将这种治疗方法从实验室转化为临床试验是 脑组织结构破坏导致移植细胞生存不利环境的挑战。许多被称为支架的材料可用于为移植细胞提供结构支撑，但可供选择的比较数据很少。在目标 1 中，我们将测试以下假设：具有不同分子组成的支架可能会影响体外人诱导多能细胞的存活或神经分化。这些数据将为后续的移植研究提供更好的支架选择。梗塞宿主组织反应，包括炎症、星形细胞增多和血管生成，也可能影响移植细胞和支架的命运。此外，这些移植物-支架-宿主相互作用可能会根据距梗塞的距离而变化。在目标 2 中，我们将测试移植细胞、支架和 hst 组织以空间动态方式相互反应的假设，这对于大鼠腔隙性中风模型中的移植物和组织结果很重要。移植物宿主神经元突触重新连接梗塞神经通路的治疗潜力也可能受到相对于受损神经束的移植位置的影响。体感丘脑皮质束的一个小的、有针对性的梗塞，与称为丘脑腔隙的人类中风类型一起发生，提供了一个理想的模型系统来评估移植物放置对丘脑皮质束重新连接的影响。在目标 3 中，我们将测试以下假设：移植物位置将通过移植物-宿主连接影响丘脑腔隙性中风大鼠模式的功能恢复。职业发展计划：我的主要导师将是干细胞神经科学家张素春，她将监督我的干细胞和神经科学方面的研究以及我的整体职业发展。我还将各派一名共同导师，专门关注中风科学、我的培训中的 K08 医师科学家方面，以及我在负责任的研究行为方面的整体职业发展和培训。我将通过细胞治疗和脑损伤恢复领域领导者的课程作业和校外实验室实习来补充导师和顾问提供的实践基础科学培训。