Molecular Mechanisms of Axonal Degeneration After White Matter Stroke

白质中风后轴突变性的分子机制

• 批准号: 8568579
• 负责人: Jason D Hinman
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8568579
• 关键词: Accounting; Acute; Affect; Award; Axon; Brain; Brain region; California; Caring; Cause of Death; Cell-Cell Adhesion; Cells; Clinical; Collaborations; Commit; Development; Development Plans; Disease; Dissection; Distant; Elements; Energy Metabolism; Energy Transfer; Environment; Event; Gene Expression; Genes; Goals; Grant; Health; Hospitals; Impaired cognition; Injury; Knowledge; Label; Lasers; Lead; Leadership; Length; Lesion; Los Angeles; MCT-1 gene; Magnetic Resonance Imaging; Maintenance; Measures; Mentors; Methodology; Modeling; Molecular; Molecular Profiling; Myelin; Neurologic; Neurology; Neurons; Oligodendroglia; Patients; Preventive; Process; Production; Psyche structure; Ranvier' s Nodes; Research; Resources; Rodent; Role; Science; Scientist; Sensory; Signal Transduction; Site; Source; Staging; Stroke; Structure; System; Systems Biology; Techniques; Therapeutic; Tissues; Training; Translating; Universities; Vascular Dementia; Vascular Diseases; Work; axonal degeneration; blood vessel occlusion; career; career development; cell type; design; disability; exome sequencing; experience; improved; in vivo; injured; laser capture microdissection; meetings; mouse model; neuronal cell body; novel; novel therapeutics; programs; public health relevance; repaired; therapeutic development; treatment strategy; white matter; white matter damage

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.

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，其中约 25% 被称为“小血管中风”，影响大脑白质，导致严重的残疾和认知障碍 衰退。磁共振成像的使用表明，白质中风会扩大，患者的残疾会加重，而这些情况通常是在患者仍在医院接受护理时进行的。这种失去治疗机会的部分原因是对白质中风后的分子事件了解甚少，特别是那些涉及脑白质独特细胞成分：轴胶质单位的分子事件。白质损伤会破坏髓鞘少突胶质细胞、轴突及其相关神经元细胞体（轴胶质单位）之间的分子连接，导致进行性轴突变性和中风扩展。这项资助的研究将采用一种新型的白质中风小鼠模型来识别轴突胶质单位内细胞间粘附和能量转移的细胞和分子机制，从而导致进行性轴突变性和中风扩张。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段的逆行作用。这些目标反映了我的近期职业目标，即更好地了解与白质中风和大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。该指导奖项将提供啮齿动物中风建模、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的具体高级培训。该培训将在转化性中风研究领域的领导者 S. Thomas Carmichael 博士的指导下进行，并由临床中风科学领域的世界领先者 Jeffrey Saver 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，将获得一份职业发展计划，提供这些分子技术的培训以及将实验室研究结果转化为治疗方法所需的策略。加州大学洛杉矶分校拥有一个大型且活跃的学术神经病学系，在培训临床医生科学家方面享有盛誉。拟议的工作还将利用加州大学洛杉矶分校在科学核心方面的可用资源以及通过神经病学系内建立的合作。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结构化和支持性的环境。