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：这个职业发展奖（CDA 2）描述了加思特里的研究和培训活动， 医学博士、博士，精神病研究、教育和临床中心的精神病学家和临床神经科学家 在弗吉尼亚州普吉特湾他的职业目标是联合收割机结合他在正电子发射方面的训练 断层扫描（PET）与新获得的和正在进行的病理生物学和转化研究的培训， 轻度创伤性脑损伤（mTBI），并加强其在神经影像学分组统计分析方面的训练。长- 他打算建立一个独立的研究项目，专注于使用分子神经成像， 加强对神经精神疾病的理解并指导治疗的发展。调研： 大约20%从伊拉克返回的军人经历过mTBI，导致躯体， 认知和行为症状，导致严重残疾和干扰工作和家庭 关系。神经炎症已经被认为是急性和慢性炎症的重要贡献者。 原始细胞mTBI的影响，并与随后的神经变性。两人都是有爆炸史的老兵 相关的mTBI和战场相关的重复性冲击mTBI小鼠模型显示持续升高， IL-6。此外，爆炸暴露的小鼠表现出持续的小胶质细胞病理学，这与 神经病理学最近在退伍军人中发现爆炸诱导的mTBI。这一建议具体 解决了需要了解，如果神经炎症是持续性后，爆炸mTBI成像 转运蛋白kDa 18（TSPO），一种经过充分验证的神经炎症生物标志物和一种相关蛋白， 小胶质细胞激活。使用PET和TSPO选择性放射性配体[18 F]DPA-714，Terry博士将对小鼠进行成像 冲击波mTBI（SA 1）后，这提供了一个独特的机会，以控制损伤的重复性和敏锐性， 根据神经炎症的离体组织病理学证据表征体内成像结果， 神经变性第二，Terry医生将在有爆炸性mTBI病史的退伍军人中使用PET对TSPO进行成像（SA 2） 以证明慢性神经炎症的存在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指标和其他生物标志物相关联。职业生涯 发展计划：该提案通过建立他的翻译和翻译能力， 在三个关键领域的临床研究专长：1）PET神经成像的转化应用，2）转化 原始细胞mTBI的生物标志物研究和临床评估，以及3）成为独立的研究者-临床医生 在VHA。专业发展活动包括：与职业导师定期举行会议， 统计学，神经炎症和PET分析的正式研究生课程;定期参与和 在mTBI和神经影像学的地方研讨会上演讲;在国家科学院的研究中演讲 两会凭借这些目标，特里博士将寻求明确区分自己作为一个独立的VA 调查员谁是独特的，从他的导师和补充，他们的努力，帮助退伍军人与 冲击波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、人类生物标志物收集和研究、小鼠爆炸方面的专家组成的高级教师 mTBI病理生物学和PET图像研究和分析。他的主要导师佩斯金德博士被公认为 在冲击波mTBI领域的领导者，并已成功地指导多名学员通过CDA独立 教师职位。库克，Innis和Muzi先生是完全资助的研究人员，他们在以下方面拥有专业知识： 小鼠疾病模型、分子生物学、神经炎症和PET神经成像和分析。他 顾问包括统计分析（Millard博士）、PET成像（Kinahan博士和Miyaoka博士）和 放射化学（Grierson和Kassiou博士）。这些调查人员已经建立了专业的合作关系 与特里博士合作，并致力于实现本文概述的目标。