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: 10449788
• 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/10449788
• 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; Measures; Mediating; Mediator of activation protein; Mentors; Mentorship; Molecular; Mus; Neurologist; Neurology; Neurons; Patient Care; Patients; Physical therapy; Physicians; Physiology; Positioning Attribute; Process; 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; 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.

这个辅导式职业发展奖的目标是促进候选人向独立的过渡 作为一名研究中风康复的分子和神经机制的内科科学家。候选人是 具有突触生理学和皮质网络研究背景的医学/博士神经科医生。该奖项将 帮助应聘者在缺血性卒中后网络恢复机制和 将有助于他转变为拥有独立实验室的调查员。该奖项还将有助于定位 实现他的长期目标的候选人，成为一名成功和多产的内科医生-科学家，领导者 在学术神经学方面，以及改善患者生活的翻译研究的调解人 死于急性脑损伤。进行拟议研究的环境非常好。这个 候选人的共同导师李振武博士是一位国际公认的科学家和神经学家，他的 在培训初级教员方面取得了卓越的成绩。候选人的职业发展计划还包括 来自多名医生的结构化指导-所有年资阶段的科学家，以及接触过丰富和 支持员工，确保应聘者在整个职业发展轨迹中都有榜样。 讲授学习，在科学会议上发表演讲，以及在负责任的研究行为方面进行严格培训 确保平衡发展。这项拟议的研究将检验轴突萌发在修复中的作用。 局部大脑皮层回路和与全球大脑网络的二次重新连接。局灶性皮质损伤后的恢复 卒中与梗死区的功能重新映射到邻近的非梗死区皮质有关。 恢复还与恢复中断的功能连接网络相关。虽然两者都 现象(局部电路重新映射和功能连接的恢复)与中风密切相关 恢复，潜在的结构底物是未知的。这个项目的目标是检验这样一个假设 轴突萌发通过局部环路的重新连接来调节皮质的重新映射。第二个假设是 来自重新映射的皮质的进一步轴突萌发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来实现连接。这个项目进一步假设 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)与行为中风的恢复程度相关。澄清驱动因素的根本机制 卒中后的网络修复将为缺血性脑损伤后的康复提供关键的见解，并将是 为未来试图利用这些机制改善中风幸存者预后的研究奠定基础。这 职业发展奖是为应聘者提供有价值的研究培训的理想机制 补充他对护理急性脑损伤患者的临床关注，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。