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: 9014381
• 负责人: TERRANCE T KUMMER
• 金额: $ 14.92万
• 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/9014381
• 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; Faculty; Filament; Focal Brain Injuries; Funding; Goals; Gold; Grant; 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; Pathology; Pathway interactions; Patients; Perforation; Pharmacodynamics; Physicians; Play; Positioning Attribute; Reporting; Research; Research Personnel; Research Training; Rupture; Sampling; Scheme; Scientist; Sensory; Severities; Social Interaction; Stroke; Subarachnoid Hemorrhage; Survivors; Synapses; System; Techniques; Testing; 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; gray matter; imaging modality; improved; injured; innovation; mortality; mouse model; nervous system disorder; neuroimaging; neuromuscular; neurosurgery; novel; novel diagnostics; pre-clinical; prognostic; public health relevance; rehabilitation strategy; research study; 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(申请人提供)：候选人：Terrance T.Kummer博士是一名基础神经学家和神经重症护理医生，他在神经肌肉突触发生领域的先前研究对我们理解哺乳动物神经肌肉接头发育中的跨突触交流做出了重要贡献。最近，Kummer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的研究。这项工作导致了一种新的出血性脑损伤机制-轴突损伤-提供了中风和脑创伤之间的意想不到的联系。Kummer博士现在正在寻求职业发展奖，以促进他的短期目标，即完成他之前研究的创新性扩展，实现作为一名研究人员的独立，并成功竞争NIH R01拨款。由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Kummer博士在这一努力中的成功至关重要。他们也是实现他的长期目标的关键一步，即通过成为该领域的领先科学贡献者来改善出血性脑损伤后的结果。Kummer博士的职业发展计划包括动物外科、行为分析和定量组织分析方面的额外培训。Kummer博士还将接受与他提出的项目和职业目标相关的扩散磁共振原理和应用方面的额外培训。他将进一步获得高级统计知识、翻译研究培训和负责任的研究指导。环境：华盛顿大学(吴)在高级神经成像研究方面装备精良，成就斐然，并以与初级研究人员合作和支持而闻名。吴的生物医学磁共振实验室配备了多台高场强、高梯度的小动物核磁共振扫描仪，由一大群备受赞誉的科学家运营。吴的以神经疾病为导向的基础科学社区是世界上最大的社区之一，聚集了大卫·霍兹曼、兰德尔·贝特曼和大卫·布罗迪等顶尖科学家，并通过霍普神经疾病中心得到了众多资金雄厚的核心实验室的支持。Kummer医生是吴的神经科和神经外科重症监护病房的主治医生，该院尤其以将创新的急性神经成像技术应用于脑损伤患者，尤其是脑出血后的患者而闻名。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：颅内动脉瘤破裂引起的蛛网膜下腔出血是脑血管损伤中最具破坏性的变种，1个月内死亡率接近50%。幸存者报告的原发残疾是认知、社交和情感缺陷，可能存在弥漫性或多灶性病理相关性，这些相关性对于标准成像模式是未知和不可见的。尽管绝大多数SAH研究集中在延迟汇编上，但影响预后的最重要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磁共振生物标记物在小鼠模型中将组织病理学定义的EBI亚型与长期行为结果联系起来，来研究SAH后早期脑损伤(EBI)的机制。我们的中心假设得到了初步数据的支持，即先进的弥散磁共振参数将识别SAH后与功能相关的病理并预测行为结果，暗示不同的EBI机制。我们将首先使用金标准定量组织学分析来确定SAH(SA1)后EBI通路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，我们将针对机械性损伤、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(SA2)的高级扩散生物标记物。最后，在我们的模型系统中，我们将通过使用这些MRI生物标记物来确定哪些EBI途径与重要的行为结果最相关，从而确定SAH(SA3)后认知、社会和情绪结果之间的机制相关性。这项研究将通过提供有关EBI的时空演变及其与长期结果的关系的基本知识，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记物，这些标记物预测与患者相关性最大的行为障碍，并与潜在的可干预的EBI途径相关联。拟议中的研究将使库默博士在先进的小动物和人体扩散磁共振领域开拓利基市场，符合他的临床专业知识，并有助于他的职业目标。