Scaffold-supported neural progenitor cell grafting to improve stroke 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，我的K 08奖的目标是获得密集的基础科学培训和指导研究，我需要建立一个R 01资助的独立基础科学实验室，这将导致这些令人兴奋的潜在治疗的后期转化研究。研究项目：中风后残疾是一个主要的公共卫生问题。脑内移植人神经前体细胞是一种有前途的潜在治疗方法，以改善中风后的恢复。将这种治疗方法从实验室转化为临床试验， 由于脑组织的结构破坏而导致移植细胞存活的不利环境。有许多称为支架的材料可用于为移植细胞提供结构支持，但很少有比较数据可供选择。在目标1中，我们将测试具有不同分子组成的支架可能影响体外人诱导多能细胞的存活或神经分化的假设。该数据将允许更好的支架选择用于后续的移植研究。包括炎症、星形细胞增多和血管生成在内的宿主组织反应也可能影响移植细胞和支架的命运。此外，这些移植物-支架-宿主相互作用可根据与梗死的距离而变化。在目标2中，我们将在大鼠腔隙性卒中模型中检验移植物细胞、支架和hst组织以空间动态方式相互反应的假设，这对移植物和组织结局很重要。移植物-宿主神经元突触重新连接梗死神经通路的治疗潜力也可能受到移植物相对于受损管道的位置的影响。一个小的，有针对性的梗死的躯体感觉丘脑皮质束，发生与人类中风类型称为丘脑腔隙，提供了一个理想的模型系统，以评估移植物放置的影响，对道重新连接。在目标3中，我们将检验移植物位置将通过移植物-宿主连接影响丘脑腔隙性卒中大鼠模型的功能恢复的假设。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，他将监督我研究的干细胞和神经科学方面以及我的整体职业发展。我还将有一个共同导师，专门专注于中风科学，K 08医生科学家方面的培训，以及我的整体职业发展和培训，在负责任的研究行为。我将补充实践基础科学培训的导师和顾问与课程和校外实验室实习的领导者在细胞治疗和脑损伤恢复领域。

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.