ADVANCED DIFFUSION BIOMARKERS OF BRAIN INJURY IN SUBARACHNOID HEMORRHAGE

 描述（由申请人提供）： 候选人：特伦斯·T博士。库默是一位基础神经科学家和神经重症监护医师，他先前在神经肌肉突触发生领域的研究为我们理解哺乳动物神经肌肉接头发育中的跨突触通讯做出了重大贡献。最近，库默博士完成了一项关于蛛网膜下腔出血（SAH）后早期脑损伤机制的动物模型和患者研究。这项工作导致了一种新的出血性脑损伤机制-轴突损伤的鉴定，这提供了中风和脑创伤之间的意外联系。库默博士现在寻求职业发展奖，以促进他的短期目标，完成他以前的研究达到独立作为一个研究人员的创新扩展，并成功地竞争NIH R 01赠款。职业发展奖提供的受保护的时间和关键研究方法的培训对库默博士在这奋进的成功至关重要。他们也是实现他的长期目标的重要一步，即通过成为该领域的主要科学贡献者来改善出血性脑损伤后的结果。库默博士的职业发展计划包括动物外科、行为分析和定量组织学分析方面的额外培训。库默博士还将接受与其拟议项目和职业目标相关的扩散MRI原理和应用方面的额外培训。他将进一步获得先进的统计知识，转化研究培训，并在研究的负责任的行为指示。工作环境：华盛顿大学（WU）在先进的神经影像学研究方面装备精良，成绩斐然，并以合作和支持初级研究人员而闻名。WU的生物医学磁共振实验室配备了多个高场强和高梯度的小动物MRI扫描仪，并由一个由著名科学家组成的大型社区运营。WU的神经系统疾病为导向的基础科学社区是世界上最大的社区之一，也是大卫霍尔茨曼，兰德尔贝特曼和大卫布罗迪等领先科学家的家园，并通过希望神经疾病中心得到众多资金充足的核心实验室的支持。库默博士是WU的神经病学和神经外科重症监护室的主治医生，该病房以创新的急性神经成像在脑损伤患者中的应用而闻名，特别是在脑出血后。总的来说，WU是理想的机构， 博士库默的职业发展和成功的建议项目。调研：颅内动脉瘤破裂引起的SAH是血管性脑损伤中最具破坏性的变异，1个月死亡率接近50%。幸存者报告的主要残疾是认知、社交和情感缺陷，可能与标准成像模式未知和不可见的弥漫性或多灶性病理学相关。虽然绝大多数SAH研究集中在延迟汇编，结果的最重要的决定因素是急性损伤的严重程度。因此，我们建议通过使用平移扩散MRI生物标志物将组织病理学定义的EBI亚型与小鼠模型中的长期行为结果联系起来来研究SAH后早期脑损伤（EBI）的机制。我们的中心假设，我们的初步数据支持，是先进的扩散MRI参数将识别功能相关的病理SAH后，预测行为的结果，涉及不同的EBI机制。我们将首先使用金标准定量组织学分析在损伤后确定的时间点确定SAH（SA 1）后EBI途径的区域贡献和时间演变。根据我们的初步研究和先前的报告，我们将针对机械损伤，微血栓形成和急性缺血。然后，我们将使用两种MRI方法（扩散峰度成像和广义q采样成像）识别和验证不同EBI途径（SA 2）的高级扩散生物标志物。最后，我们将通过使用这些MRI生物标志物来确定SAH（SA 3）后认知，社会和情感结果的机制相关性，以确定哪些EBI途径与我们的模型系统中的重要行为结果最相关。这项研究将通过提供有关EBI的时空演变及其与长期结局的关系的基础知识，对SAH领域产生持续的影响。它将进一步验证创新的翻译生物标志物，这些生物标志物预测与患者相关性最大的行为障碍，并与潜在的可干预EBI途径相关联。拟议的研究将使库默博士能够根据其临床专业知识在先进的小动物和人类扩散MRI中开拓一个利基市场，并有利于其职业目标。

 DESCRIPTION (provided by applicant): Candidate: Dr. Terrance T. Kummer is a basic neuroscientist and neurocritical care physician whose prior research in the field of neuromuscular synaptogenesis contributed significantly to our understanding of trans- synaptic communication in the development of the mammalian neuromuscular junction. Recently, Dr. Kummer completed a study of early brain injury mechanisms following subarachnoid hemorrhage (SAH) in an animal model and in patients. This work led to the identification of a novel hemorrhagic brain injury mechanism- axonal injury-that provided an unexpected connection between stroke and brain trauma. Dr. Kummer now seeks a career development award to facilitate his short-term goals of completing an innovative extension of his prior studies reaching independence as a researcher, and successfully competing for an NIH R01 grant. The protected time, and training in crucial research approaches provided by a career development award are essential to Dr. Kummer's success in this endeavor. They are also an essential step towards accomplishing his long-term goal of improving outcomes after hemorrhagic brain injury by becoming a leading scientific contributor to his field. Dr. Kummer's career development plan includes additional training in animal surgery, behavioral analysis, and quantitative histological analysis. Dr. Kummer will also undertake additional training in the principles and application of diffusion MRI relevant to his proposed project and career goals. He will further acquire advanced statistical knowledge, translational research training, and instruction in the responsible conduct of research. Environment: Washington University (WU) is exceptionally well-equipped and accomplished in advanced neuroimaging research, and has a reputation for collaboration and support of junior investigators. The Biomedical Magnetic Resonance Laboratory at WU is equipped with multiple high-field strength and high- gradient small animal MRI scanners, and is operated by a large community of acclaimed scientists. The neurological disease-oriented basic science community at WU is one of the largest in the world, and home to leading scientists such as David Holtzman, Randall Bateman, and David Brody, and is supported by numerous well-funded core laboratories through the Hope Center for Neurological Disorders. The Neurology and Neurosurgery Intensive Care Unit at WU, where Dr. Kummer is an attending, is particularly well-known for the application of innovative, acute neuroimaging to brain injured patients, especially after brain hemorrhage. Overall, WU is the ideal institution for Dr. Kummer's career development and the success of the proposed project. Research: SAH from the rupture of an intracranial aneurysm is the most devastating variant of vascular brain injury, carrying a 1-month mortality rate of nearly 50%. The primary disabilities reported by survivors are cognitive, social, and emotional deficits with likely diffuse or multifocal pathologial correlates that are unknown and invisible to standard imaging modalities. Although the great majority of SAH research focuses on delayed compilations, the most important determinant of outcome is the severity of the acute injury. We therefore propose to investigate the mechanisms of early brain injury (EBI) after SAH by linking histopathologically- defined EBI subtypes to long-term behavioral outcomes in a mouse model using translational diffusion MRI biomarkers. Our central hypothesis, supported by our preliminary data, is that advanced diffusion MRI parameters will identify functionally-relevant pathology after SAH and predict behavioral outcomes, implicating distinct EBI mechanisms. We will first determine the regional contribution and temporal evolution of EBI pathways after SAH (SA1) using gold-standard quantitative histological analysis at defined time points post- injury. Based on our preliminary studies and prior reports, we will target mechanical injury, microthrombosis, and acute ischemia. We will then identify and validate advanced diffusion biomarkers of distinct EBI pathways (SA2) using two MRI approaches, diffusion kurtosis imaging and generalized q-sampling imaging. Lastly, we will identify the mechanistic correlates of cognitive, social, and emotional outcomes after SAH (SA3) by using these MRI biomarkers to determine which EBI pathways best correlate with important behavioral outcomes in our model system. This study will have a sustained impact on the SAH field by supplying fundamental knowledge about the spatial and temporal evolution of EBI and its relationship to long-term outcomes. It will furthermore validate innovative translational biomarkers that predict behavioral impairments with the greatest relevance to patients, and are linked to potentially intervenable EBI pathways. The proposed studies will position Dr. Kummer to exploit a niche in advanced small animal and human diffusion MRI in line with his clinical expertise and conducive to his career goals.