Scaffold-supported neural progenitor cell grafting to improve stroke recovery

点击翻译按钮获取中文摘要

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.