ADVANCED DIFFUSION BIOMARKERS OF BRAIN INJURY IN SUBARACHNOID HEMORRHAGE

蛛网膜下腔出血脑损伤的先进扩散生物标志物

• 批准号: 9312333
• 负责人: TERRANCE T KUMMER
• 金额: $ 17.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312333
• 关键词: Acute; Address; Affect; American; Animal Model; Animals; Arteries; Basic Science; Behavioral; Biological Markers; Biological Models; Brain; Brain Injuries; Brain hemorrhage; Caring; Cerebrovascular Spasm; Cerebrovascular Trauma; Clinical; Clinical Research; Cognition; Cognitive; Collaborations; Communication; Communities; Complex; Data; Development; Development Plans; Diagnosis; Diagnostic; Diffuse; Diffuse Brain Injury; Diffusion; Diffusion Magnetic Resonance Imaging; Emotional; Employment; Environment; Etiology; Event; Evolution; Filament; Focal Brain Injuries; Funding; Goals; Gold; Grant; Histologic; Histopathology; Home environment; Hour; Human; Image; Impaired cognition; Injury; Institution; Instruction; Intensive Care Units; Intervention; Intracranial Aneurysm; Ischemia; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Link; Magnetic Resonance; Magnetic Resonance Imaging; Measurable; Mechanics; Methods; Modality; Modeling; Monitor; Motor; Neurology; Neuromuscular Junction; Operative Surgical Procedures; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Perforation; Pharmacodynamics; Physicians; Play; Positioning Attribute; Radiology Specialty; Reporting; Research; Research Personnel; Research Training; Rupture; Sampling; Scheme; Scientist; Sensory; Severities; Social Interaction; Stroke; Subarachnoid Hemorrhage; Survivors; Synapses; System; Teacher Professional Development; Techniques; Therapeutic Trials; Time; Training; Translational Research; Traumatic Brain Injury; United States; United States National Institutes of Health; Universities; Variant; Washington; Work; axon injury; base; behavioral impairment; behavioral outcome; career; career development; contrast enhanced; cost; disability; emotion regulation; experimental study; gray matter; imaging modality; imaging potential; imaging study; improved; improved outcome; innovation; magnetic resonance imaging biomarker; mortality; mouse model; nervous system disorder; neurobehavioral; neuroimaging; neuromuscular; neurosurgery; novel; novel diagnostics; pre-clinical; predictive marker; prognostic assays; public health relevance; rehabilitation strategy; responsible research conduct; social; success; synaptogenesis; targeted treatment; white matter

 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.

 描述（由适用提供）：候选人：Terrance T. Kummer博士是基本的神经科学家和神经政治护理物理学，其先前在神经肌肉突触发生领域的研究对我们对乳腺神经肌肉发育发展中跨性突触通信的理解做出了重大贡献。最近，Kummer博士在动物模型和患者中完成了蛛网膜下腔出血（SAH）后早期脑损伤机制的研究。这项工作导致了一种新型出血性脑损伤机制 - 轴突损伤 - 在中风和脑外伤之间产生了意外的联系。 Kummer博士现在寻求一项职业发展奖，以支持他的短期目标，即完成他先前作为研究人员独立的研究的创新扩展，并成功争夺NIH R01赠款。由职业发展奖提供的受保护时间和关键研究方法的培训对于库默博士在这项工作中的成功至关重要。这也是实现自己的长期目标的重要一步，即通过成为他领域的主要科学贡献者，在出血性脑损伤后改善结果。 Kummer博士的职业发展计划包括动物外科手术，行为分析和定量组织学分析的其他培训。 Kummer博士还将在与他的拟议项目和职业目标相关的扩散MRI原理和应用方面进行其他培训。他将进一步获得高级统计知识，翻译研究培训以及负责任的研究的指导。环境：华盛顿大学（WU）在高级神经影像研究方面具有出色的设备齐全，并且在初级研究人员的协作和支持方面享有声誉。 WU的生物医学磁共振实验室等效，具有多个高场强度和高梯度的小动物MRI扫描仪，并且由大型著名科学家社区运营。 WU的以神经性疾病为导向的基础科学界是世界上最大的基础科学界之一，也是戴维·霍尔茨曼（David Holtzman），兰德尔·贝特曼（Randall Bateman）和戴维·布罗迪（David Brody）等领先科学家的所在地，并通过希望神经疾病的希望中心得到了众多资金丰富的核心实验室的支持。库默（Kummer）博士参加的WU的神经病学和神经外科重症监护病房（Kummer）是一名参与者，尤其是将创新的，急性神经影像应用于脑损伤患者，尤其是在脑出血后。总体而言，吴是理想的机构 Kummer博士的职业发展和拟议项目的成功。研究：SAH因颅内动脉瘤的破裂是血管脑损伤的最具破坏性的变体，其1个月死亡率接近50％。生存报告的主要残疾是认知，社会和情绪缺陷，可能是弥漫性或多灶性病理学相关性，这些相关性是未知且对标准成像方式看不见的。尽管SAH的绝大部分研究重点是延迟汇编，但最重要的结果决定是急性损伤的严重程度。因此，我们建议使用翻译扩散MRI生物标志物将历史定义的EBI亚型与长期行为结果联系起来，以研究SAH后早期脑损伤（EBI）的机制。我们的初步数据支持的中心假设是，高级扩散MRI参数将在SAH后识别与功能相关的病理，并预测行为结果，隐含的不同EBI机制。我们将首先使用在伤害后定义的时间点上使用金标准的定量组织学分析来确定SAH（SA1）后EBI途径的区域贡献和临时演变。根据我们的初步研究和先前的报道，我们将针对机械损伤，微栓性和急性缺血。然后，我们将使用两种MRI方法，扩散峰度成像和广义Q采样成像来识别和验证不同EBI途径（SA2）的高级扩散生物标志物（SA2）。最后，我们将通过使用这些MRI生物标志物来确定哪些EBI途径与模型系统中重要的行为结果最有效，我们将确定SAH（SA3）后认知，社会和情感结果的机理相关性。这项研究将通过提供有关EBI的空间和临时演变及其与长期结果的关系的基本知识，从而对SAH领域产生持续的影响。它将验证创新的翻译生物标志物，这些生物标志物可以预测与患者最相关的行为障碍，并且与潜在的可间歇性EBI途径有关。拟议的研究将使Kummer博士在高级小型动物和人类扩散MRI中利用一个利基，这符合其职业目标的临床专业知识和导电性。