Molecular Mechanisms of Axonal Degeneration After White Matter Stroke

描述（由申请人提供）：中风是美国死亡和残疾的主要原因。在每年795，000例新发中风中，约25%的这些中风被称为“小血管中风”，影响脑白色物质，产生显著的残疾和认知障碍。 下降磁共振成像的使用表明，白色物质中风扩大和病人的残疾进展，往往是在病人仍然在医院的照顾。这种治疗机会的丧失部分是由于对白色物质中风后的分子事件缺乏了解，特别是那些涉及脑白色物质独特细胞成分的分子事件：轴突胶质单位。对白色物质的损伤破坏了髓鞘化少突胶质细胞、轴突及其相关神经元细胞体（轴突胶质单位）之间的分子连接，导致进行性轴突变性和中风扩大。这项研究将采用一种新的小鼠白色物质中风模型，以确定细胞-细胞粘附和轴突单位内的能量转移，导致进行性轴突变性和中风扩展的细胞和分子机制。此外，将确定白色物质卒中对远离损伤部位的神经元细胞体的近端轴突段的逆行影响。这些目标反映了我近期的职业目标，即更好地理解与白色物质中风和脑微血管疾病相关的分子事件。从长远来看，我计划利用这些知识来设计治疗中风的新分子疗法，通过我的研究，治疗开发和学术领导来减轻中风和中风相关残疾的负担。该指导奖将提供啮齿动物中风建模，激光捕获显微切割，RNAseq外显子组测序和体内基因操作策略的特定高级培训。本培训将在S博士指导下进行。托马斯卡迈克尔，在转化中风研究的领导者和共同指导博士杰弗里储蓄，在临床中风科学的世界领导者。提供这些分子技术培训的职业发展计划和将实验室研究结果转化为治疗所需的策略将通过与这些导师的定期会议，精心挑选的课程和实践经验获得。加州大学洛杉矶分校有一个庞大而活跃的学术神经病学系，在培训临床科学家方面得到了广泛认可。拟议的工作还将利用加州大学洛杉矶分校的科学核心资源，并通过神经病学系内的既定合作。UCLA神经病学系致力于我的学术生涯的进步，并将为我的职业生涯的早期阶段提供一个结构化和支持性的环境。

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and disability in the US. Of the 795,000 new strokes per year, approximately 25% of these strokes are termed "small vessel strokes" affecting brain white matter, producing significant disability and cognitive decline. The use of magnetic resonance imaging demonstrates that white matter strokes expand and patient's disability progresses, often while patients remain under care in the hospital. This lost therapeutic opportunity is due, in part, to a poor understanding of the molecular events that follow white matter stroke, particularly those that involve the unique cellular elements of brain white matter: the axoglial unit. Injury to white matter disrupts the molecular connection between the myelinating oligodendrocyte, the axon, and its associated neuronal cell body (the axoglial unit) resulting in progressive axonal degeneration and stroke expansion. Studies in this grant will employ a novel mouse model of white matter stroke to identify the cellular and molecular mechanisms of cell-cell adhesion and energy transfer within the axoglial unit that lead to progressive axonal degeneration and stroke expansion. In addition, the retrograde effects of white matter stroke on the proximal axonal segment of the neuronal cell body far from the site of injury will be determined. These goals reflect my immediate career objectives of achieving an improved understanding of the molecular events associated with white matter stroke and micro vascular disease of the brain. Over the long-term, I plan to use this knowledge to design new molecular therapeutics for the treatment of stroke, acting to reduce the burden of stroke and stroke-related disability through my research, therapeutic development, and academic leadership. This mentored award will provide specific advanced training in rodent stroke modeling, laser capture micro dissection, RNAseq exome sequencing, and in vivo gene manipulation strategies. This training will be conducted under the direction of Dr. S. Thomas Carmichael, a leader in translational stroke research and co-mentored by Dr. Jeffrey Saver, a world leader in clinical stroke science. A career development plan providing training in these molecular techniques and the strategies needed to translate bench findings into therapeutics will be acquired through regular meetings with these mentors, carefully selected coursework, and hands-on experience. The University of California Los Angeles has a large and active academic neurology department that is well-recognized for training clinician-scientists. The proposed work will also take advantage of the resources available at UCLA in scientific cores and through established collaborations within the Department of Neurology. The UCLA Department of Neurology is committed to the advancement of my academic career and will provide a structured and supportive environment for the early stage of my career.