Role of Axonal Sprouting Mediated Network Reorganization in Stroke Recovery

轴突萌芽介导的网络重组在中风恢复中的作用

• 批准号: 10605288
• 负责人: Asher Jefferson Albertson
• 金额: $ 19.87万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605288
• 关键词: Acute Brain Injuries; Address; Adult; Automobile Driving; Award; Basic Science; Behavioral; Biological Assay; Brain; Brain region; Cerebrum; Clinical; Complement; Development; Development Plans; Distant; Doctor of Philosophy; Ensure; Environment; Exposure to; Faculty; Follow-Up Studies; Functional Imaging; Future; Gene Transfer; Genetic Engineering; Global Change; Goals; Growth Associated Protein 43; Image; Infarction; International; Ischemia; Ischemic Brain Injury; Ischemic Stroke; K-Series Research Career Programs; Laboratories; Learning; Maps; Measures; Mediating; Mediator; Mentors; Mentorship; Molecular; Mus; Neurologist; Neurology; Neurons; Patient Care; Patients; Physical therapy; Physicians; Physiology; Positioning Attribute; Process; Productivity; Proteins; Recovery; Recovery of Function; Research; Research Personnel; Research Training; Role; Scientist; Sensory; Somatosensory Cortex; Stroke; Structure; Synapses; Testing; Thalamic structure; Time; Training; Translating; Translational Research; United States; Viral; Viral Genes; Walking; Work; axonal sprouting; calcium indicator; career; career development; cortex mapping; disability; effective therapy; experience; fluorescence imaging; functional restoration; imaging platform; imaging study; improved; improved outcome; insight; knock-down; meetings; neuronal circuitry; neurophysiology; novel; post stroke; repaired; responsible research conduct; restoration; role model; sensory stimulus; skills; small hairpin RNA; somatosensory; stroke patient; stroke recovery; stroke survivor; supportive environment; translational study

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.

这个指导职业发展奖的目标是促进候选人的过渡到独立 作为一名研究中风恢复的分子和神经机制的医生科学家。候选人是 一位具有突触生理学和皮质网络研究背景的医学博士/博士神经学家。该奖项将 帮助候选人获得缺血性中风后网络恢复机制的研究经验， 这将有助于他过渡到一个独立实验室的研究者。该奖项还将有助于定位 候选人，以实现他的长期目标，成为一个成功的和富有成效的医生，科学家，领导者， 在学术神经病学，和转化研究的调解人，改善患者的生活遭受 急性脑损伤进行拟议研究的环境是杰出的。的 候选人的共同导师，Jin-Moo Lee博士，是一位国际公认的科学家和神经学家， 在培训初级教师方面有着卓越的记录。候选人的职业发展计划还包括 来自多个医生-科学家的结构化指导，这些医生-科学家处于资历的各个阶段， 支持教师，确保候选人沿着职业轨迹的全方位的榜样。 教学式的学习，在科学会议上的演讲，以及在负责任的研究行为方面的严格培训 确保均衡发展。这项拟议中的研究将检查轴突发芽在修复中的作用 局部皮层回路和与全球大脑网络的二次重新连接。局灶性皮质后恢复 中风与梗塞区域的功能重新映射到相邻的非梗塞皮质有关。 恢复也与恢复中断的功能连接的网络有关。虽然这两 一些现象（局部回路重新映射和功能连接的恢复）与中风密切相关 恢复，底层结构基底是未知的。这个项目的目标是测试假设， 轴突发芽通过局部回路的重新连接介导皮质重映射。次要假设是， 源自重新映射的皮层的进一步轴突发芽介导全脑功能的恢复， 通过将断开的电路重新整合到全球网络中来实现连通性。该项目进一步假设， 这两个过程的恢复程度（局部重新映射和功能连接的恢复） 网络）与行为中风恢复的程度相关。澄清推动发展的基本机制 中风后的网络修复将为缺血性脑损伤后的恢复提供重要的见解， 为未来研究试图利用这些机制来改善中风幸存者的预后奠定了基础。这 职业发展奖是一个理想的机制，为候选人提供有价值的研究培训， 补充他对急性脑损伤患者的临床护理，并将帮助他发展一套技能 将基础科学发现转化为中风患者的有效疗法。