Molecular Mechanisms of Axonal Degeneration After White Matter Stroke

描述(申请人提供)：中风在美国是导致死亡和残疾的主要原因。在每年795,000例新中风中，大约25%的中风被称为影响脑白质、导致严重残疾和认知能力的“小血管中风” 拒绝。磁共振成像的使用表明，白质中风扩大和患者的残疾进展，通常是在患者仍在医院接受治疗的情况下。这种失去的治疗机会在一定程度上是由于对脑白质中风后的分子事件缺乏了解，特别是那些涉及脑白质的独特细胞元素：轴突单位的事件。白质损伤破坏了髓鞘少突胶质细胞、轴突及其相关神经元细胞体(轴突单位)之间的分子连接，导致进行性轴突变性和卒中扩张。这项拨款的研究将采用一种新的白质中风小鼠模型，以确定导致进行性轴突变性和中风扩大的轴突单位内细胞-细胞黏附和能量转移的细胞和分子机制。此外，还将确定白质中风对远离损伤部位的神经元细胞体近端轴突的逆行影响。这些目标反映了我的直接职业目标，即更好地理解与脑白质中风和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为中风的治疗设计新的分子疗法，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。该指导奖将在啮齿动物中风建模、激光捕获显微解剖、RNAseq外显子组测序和体内基因操作策略方面提供具体的高级培训。这项培训将在S·托马斯·卡迈克尔博士的指导下进行，卡迈克尔博士是翻译中风研究的领导者，并由临床中风科学的世界领导者杰弗里·萨弗博士共同指导。通过与这些导师的定期会议、精心挑选的课程和实践经验，将获得职业发展计划，提供这些分子技术方面的培训，以及将板凳研究成果转化为治疗学所需的战略。加州大学洛杉矶分校拥有一个庞大而活跃的学术神经病学系，该系在培养临床医生-科学家方面广为人知。这项拟议的工作还将利用加州大学洛杉矶分校现有的科学核心资源，并通过神经病学系内建立的合作关系。加州大学洛杉矶分校神经病学系致力于促进我的学术生涯，并将为我职业生涯的早期阶段提供一个有条理的、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.