Role of Axonal Sprouting Mediated Network Reorganization in Stroke Recovery

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The goal of this mentored career development award is to facilitate the candidate’s transition to independence as a physician-scientist studying the molecular and neuronal mechanisms of stroke recovery. The candidate is an MD/PhD neurologist with a background in synaptic physiology and cortical network research. The award will help the candidate gain research experience in the mechanisms of network recovery after ischemic stroke and will facilitate his transition to an investigator with an independent laboratory. The award will also help position the candidate to achieve his long term goal of becoming a successful and productive physician-scientist, a leader in academic neurology, and a mediator of translational research which improves the lives of patients suffering from acute brain injury. The environment in which the proposed research will be conducted is outstanding. The candidate’s co-mentor, Dr. Jin-Moo Lee, is an internationally recognized scientist and neurologist with a proven track record of excellence in training junior faculty. The candidate’s career development plan also includes structured mentorship from multiple physician-scientists at all stages of seniority and exposure to a rich and supportive faculty, ensuring the candidate has role models along the full spectrum of the career trajectory. Didactic learning, presentation at scientific meetings, and rigorous training in the responsible conduct of research will ensure balanced development. The proposed research will examine the role of axonal sprouting in restoration of both local cortical circuits and secondary reconnection to global brain networks. Recovery after focal cortical stroke is associated with remapping of the function of the infarcted region to adjacent, non-infarcted cortex. Recovery is also associated with restoration of disrupted functionally connected networks. While both phenomena (local circuit remapping and restoration of functional connectivity) are strongly associated with stroke recovery, the underlying structural substrate is unknown. The goal of this project is to test the hypothesis that axonal sprouting mediates cortical remapping via reconnection of local circuits. A secondary hypothesis is that further axonal sprouting originating from the remapped cortex mediates restoration of whole-brain functional connectivity by reintegrating the disconnected circuit into global networks. This project further hypothesizes that the degree of recovery of these two processes (local remapping and restoration of functionally connected networks) correlates to the degree of behavioral stroke recovery. Clarifying the underlying mechanisms driving network repair after stroke will provide crucial insights into recovery after ischemic brain injury and will be the basis for future studies attempting to harness these mechanisms to improve outcomes for stroke survivors. This career development award is an ideal mechanism to provide the candidate with valuable research training to complement his clinical focus on caring for patients with acute brain injury and will help him develop a skill set for translating basic science discoveries into effective therapies for patients suffering from stroke.