Molecular imaging of neuroinflammation in repetitive mild traumatic brain injury

重复性轻度创伤性脑损伤中神经炎症的分子影像

• 批准号: 10417036
• 负责人: Garth Terry
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417036
• 关键词: Acute; Address; Affect; Afghanistan; Area; Autopsy; Basic Science; Behavioral; Behavioral Symptoms; Biological Markers; Blast Injuries; Brain; Brain Pathology; Brain imaging; Cerebrospinal Fluid; Characteristics; Chronic; Chronic Headaches; Clinical; Clinical Data; Clinical Research; Clinical assessments; Cognitive; Collaborations; Collection; Conflict (Psychology); Data; Development; Development Plans; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease model; Doctor of Philosophy; Education; Environment; Faculty; Family Relationship; Foundations; Functional Magnetic Resonance Imaging; Funding; Goals; Gold; Grant; Healthcare; Human; Image; Immunohistochemistry; Impairment; Inflammation; Injury; Iraq; K-Series Research Career Programs; Knowledge; Laboratories; Learning; Measures; Mental disorders; Mentors; Microglia; Microscopic; Military Personnel; Modality; Molecular; Molecular Biology; Morphology; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neuropsychology; Neurosciences; Occupations; Outcome Measure; Pathology; Pharmacotherapy; Positioning Attribute; Positron-Emission Tomography; Process; Proteins; Psychiatrist; Quality of life; Radiochemistry; Recording of previous events; Research; Research Activity; Research Personnel; Rest; Risk; Role; Sampling; Schedule; Statistical Data Interpretation; Structural defect; Symptoms; Testing; Time; Training; Training Activity; Translational Research; Veterans; blast exposure; career; career development; chronic traumatic encephalopathy; clinical center; clinically relevant; cooking; density; design; disability; experience; faculty research; fluorodeoxyglucose positron emission tomography; improved; in vivo; in vivo imaging; meetings; mild traumatic brain injury; molecular imaging; mouse model; multidisciplinary; neuroimaging; neuroimaging marker; neuroinflammation; neuropathology; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; parametric imaging; persistent symptom; pre-clinical; programs; quantitative imaging; radioligand; research clinical testing; senior faculty; service member; skills; sound; statistics; success; symposium; tau Proteins; tau-1; therapeutic development; training project; translational applications; translational approach; uptake

Candidate: This Career Development Award (CDA2) describes research and training activities for Garth Terry, MD, PhD, a psychiatrist and clinical neuroscientist in the Mental Illness Research, Education, and Clinical Center at VA Puget Sound. His immediate career goal is to combine his established training in positron emission tomography (PET) with newly acquired and ongoing training in the pathobiology and translational research of mild traumatic brain injury (mTBI) and strengthen his training in group-wise neuroimage statistical analysis. Long- term, he intends to establish an independent research program focused on using molecular neuroimaging to enhance understanding and guide therapeutic development for neuropsychiatric disorders. Research: Approximately 20% of service members returning from Iraq have experienced mTBI resulting in somatic, cognitive, and behavioral symptoms leading to substantial disability and interference with job and family relationships. Neuroinflammation has been implicated as an important contributor to the acute and chronic effects of blast mTBI, and is associated with subsequent neurodegeneration. Both Veterans with history of blast- related mTBI and a battlefield-relevant mouse model of repetitive blast mTBI demonstrate persistently elevated IL-6. Furthermore, blast-exposed mice demonstrate persistent microglial pathology that is strikingly similar to the neuropathology very recently identified in Veterans with blast-induced mTBI. This proposal specifically addresses the need to understand if neuroinflammation is persistent following blast mTBI by imaging the translocator protein kDa 18 (TSPO), a well-validated biomarker of neuroinflammation and a protein associated with microglial activation. Using PET and the TSPO selective radioligand [18F]DPA-714, Dr. Terry will image mice following blast mTBI (SA1), which provides a unique opportunity to control injury repetition and acuity, and to characterize in vivo imaging results against ex vivo histopathological evidence of neuroinflammation and neurodegeneration. Second, Dr. Terry will image TSPO using PET in Veterans with a history of blast mTBI (SA2) to demonstrate the presence of chronic neuroinflammation. Resulting quantitative images of neuroinflammation will be correlated against clinical measures and other biomarkers already collected from those Veterans. Career Development Plan: This proposal serves Dr. Terry's short- and long-term goals by building his translational and clinical research expertise in three critical areas: 1) translational application of PET neuroimaging, 2) translational biomarker study and clinical assessments of blast mTBI, and 3) become an independent researcher-clinician within VHA. Professional development activities include: routinely scheduled meetings with career mentors, formal graduate coursework in statistics, neuroinflammation, and PET analysis; regular participation and presentation for local seminars in mTBI and neuroimaging; and presentation of research at national scientific conferences. By virtue of these goals, Dr. Terry will seek to clearly differentiate himself as an independent VA investigator who is both unique from his mentors and complementary to their efforts in helping Veterans with blast mTBI. Environment: Dr. Terry's training will be guided by an exceptionally multidisciplinary mentoring team comprised of senior faculty who are experts in blast mTBI, human biomarker collection and study, mouse blast mTBI pathobiology, and PET image research and analysis. His primary mentor, Dr. Peskind, is recognized as a leader in the field of blast mTBI and has successfully mentored multiple trainees through CDA to independent faculty position. Co-mentors Drs. Cook, Innis, and Mr. Muzi are fully-funded research faculty with expertise in mouse models of disease, molecular biology, neuroinflammation, and PET neuroimaging and analysis. His consultants include experts in in statistical analysis (Dr. Millard), PET imaging (Drs. Kinahan and Miyaoka), and radiochemistry (Drs. Grierson and Kassiou). These investigators have established professional collaborations with Dr. Terry and are invested in the success of the aims outlined herein.

候选人：该职业发展奖（CDA2）描述了Garth Terry的研究和培训活动， 医学博士，PhD，精神病医生和临床神经科学家的精神疾病研究，教育和临床中心 在VA Puget Sound。他的直接职业目标是结合他在正电子排放方面既定的培训 在病理生物学和转化研究中进行新获得和正在进行的培训的断层扫描（PET） 轻度创伤性脑损伤（MTBI），并加强了他在小组神经图像统计分析中的训练。长的- 术语，他打算建立一个专注于使用分子神经影像的独立研究计划 增强和指导神经精神疾病的治疗发展。研究： 从伊拉克返回的服务成员中，约有20％经历了MTBI，导致了躯体， 认知和行为症状导致严重的残疾和干扰工作和家庭 关系。神经炎症已被牵涉到急性和慢性的重要因素 BLAST MTBI的影响，与随后的神经变性有关。两位具有爆炸历史的退伍军人 - 相关的MTBI和与战场相关的重复性爆炸MTBI的鼠标模型持续升高 IL-6。此外，暴露于爆炸的小鼠表现出持续的小胶质细胞病理学，与 神经病理学最近在具有爆炸诱导的MTBI的退伍军人中发现。该提案专门 解决了通过成像MTBI之后的神经炎症是否持续存在的需要 转运蛋白KDA 18（TSPO），一种精心验证的神经炎症和蛋白相关的生物标志物 与小胶质细胞激活。使用PET和TSPO选择性放射线[18F] DPA-714，Terry博士将成像小鼠 在Blast MTBI（SA1）之后，它为控制伤害重复和敏锐度提供了独特的机会，并 表征了体内成像结果，反对神经炎症的体内组织病理学证据 神经变性。其次，特里博士将使用PET在具有Blast MTBI史的退伍军人中使用PET对TSPO进行图像（SA2） 证明存在慢性神经炎症。产生的神经炎症的定量图像 将与已经从这些退伍军人那里收集的临床措施和其他生物标志物相关。职业 发展计划：该提案通过建立他的翻译和 在三个关键领域的临床研究专业知识：1）PET神经影像的翻译应用，2）翻译 生物标志物研究和BLAST MTBI的临床评估，3）成为独立的研究人员 - 阵容官员 在VHA内。专业发展活动包括：与职业导师的定期会议， 统计，神经炎症和宠物分析的正式研究生课程；定期参与 MTBI和神经影像学的本地研讨会的演讲；以及在国家科学的研究表现 会议。根据这些目标，特里博士将寻求明确将自己区分为独立的VA 调查员既是他的导师，又是对帮助退伍军人的努力的补充 爆炸mtbi。环境：特里博士的培训将由一个非常多学科的指导团队指导 由爆炸MTBI专家，人类生物标志物收集和学习，鼠标BLAST的专家组成 MTBI病理生物学和PET图像研究和分析。他的主要导师Peskind博士被认为是 在Blast MTBI领域的领导者，并成功地通过CDA指导了多名学员 教师职位。联合委员会博士。库克（Cook），因尼斯（Innis）和穆兹（Muzi）先生是全资金的研究学院，拥有专业知识 疾病的小鼠模型，分子生物学，神经炎症以及PET神经影像学和分析。他的 顾问包括统计分析专家（Millard博士），PET Imaging（Kinahan博士和Miyaoka）和 放射化学（Grierson和Kassiou博士）。这些调查人员建立了专业合作 与特里博士一起，并投入了本文概述的目标的成功。