Scaffold-supported neural progenitor cell grafting to improve stroke recovery

描述(申请人提供)：我的长期目标是通过对神经细胞移植等生物疗法的基础和翻译研究来促进中风患者的康复。由于我的背景是临床研究，我获得K08奖的目标是获得我所需的密集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，这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：中风后残疾是一个主要的公共卫生问题。脑内移植人神经前体细胞是促进卒中后康复的一种有前途的潜在治疗方法。将这种疗法从实验室转化为临床试验是 受到脑组织结构破坏造成的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，我们将检验不同分子组成的支架可能会影响体外培养的人诱导多能细胞存活或神经分化的假设。这一数据将为后续的嫁接研究提供更好的支架选择。梗死宿主组织的反应，包括炎症、星形胶质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-宿主的相互作用可能会因离梗塞的距离不同而不同。在目标2中，我们将检验一个假设，即移植物细胞、支架和hst组织以空间动态的方式相互响应，这对腔隙卒中大鼠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死神经通路的治疗潜力也可能受到移植物相对于受损神经束的位置的影响。在人类卒中类型丘脑陷窝中发生的躯体感觉丘脑皮质束小的靶向性梗塞，为评估移植物置入对束重建的影响提供了一个理想的模型系统。在目标3中，我们将验证移植物位置将通过移植物-宿主连接影响丘脑腔隙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整个职业发展。我还将有一名共同导师，每人专门专注于中风科学、K08医生-科学家方面的培训，以及我全面的职业发展和负责任的研究行为培训。我将补充来自导师和顾问的实践基础科学培训，以及来自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。

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.