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、哲学博士、精神疾病研究、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。他的近期职业目标是将他在正电子发射方面的既定训练结合起来 断层扫描（PET），并在病理生物学和转化研究方面新获得并正在进行培训 轻度创伤性脑损伤（mTBI）并加强他在分组神经图像统计分析方面的训练。长的- 学期中，他打算建立一个独立的研究项目，专注于利用分子神经成像技术 增强对神经精神疾病的理解并指导治疗发展。研究： 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并干扰工作和家庭 关系。神经炎症被认为是急性和慢性疾病的重要促成因素 冲击波 mTBI 的影响，并与随后的神经退行性变相关。两位都有爆炸历史的退伍军人 相关 mTBI 和战场相关小鼠模型的重复爆炸 mTBI 表现出持续升高 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 最近在患有爆炸引起的 mTBI 的退伍军人中发现了神经病理学。该提案具体 解决了通过对 mTBI 进行成像来了解神经炎症是否持续存在的需要 易位蛋白 kDa 18 (TSPO)，一种经过充分验证的神经炎症生物标志物和相关蛋白 与小胶质细胞激活。 Terry 博士使用 PET 和 TSPO 选择性放射性配体 [18F]DPA-714 对小鼠进行成像 冲击波 mTBI (SA1) 后，它提供了一个独特的机会来控制损伤重复和严重性，并 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。其次，Terry 博士将使用 PET 对有 mTBI 病史的退伍军人进行 TSPO 成像 (SA2) 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测量和其他生物标志物相关联。职业 发展计划：该提案通过建立特里博士的转化和发展能力来服务于他的短期和长期目标。 三个关键领域的临床研究专业知识：1) PET 神经影像的转化应用，2) 转化 母细胞 mTBI 的生物标志物研究和临床评估，以及 3) 成为一名独立的研究人员-临床医生 在VHA内。职业发展活动包括：与职业导师定期举行的会议， 统计学、神经炎症和 PET 分析方面的正式研究生课程；定期参与和 为当地 mTBI 和神经影像学研讨会做演讲；并在国家科学界展示研究成果 会议。凭借这些目标，特里博士将寻求将自己作为一名独立的 VA 明确区分出来 调查员与他的导师相比是独一无二的，并且与他们帮助退伍军人的努力相辅相成 急变 mTBI。环境：特里博士的培训将由一支出色的多学科指导团队指导 由稻瘟病 mTBI、人类生物标志物收集和研究、小鼠稻瘟病专家组成的高级教师组成 mTBI病理学，以及PET图像研究和分析。他的主要导师佩斯金德博士被认为是 爆炸 mTBI 领域的领导者，并已成功指导多名学员通过 CDA 成为独立的 教职职务。共同导师博士。库克、伊尼斯和穆兹先生是拥有全额资助的研究人员，在以下领域拥有专业知识： 疾病小鼠模型、分子生物学、神经炎症以及 PET 神经成像和分析。他的 顾问包括统计分析专家（Millard 博士）、PET 成像专家（Kinahan 和 Miyaoka 博士）以及 放射化学（Grierson 博士和 Kassiou 博士）。这些研究人员建立了专业合作 与特里博士合作，并致力于本文概述的目标的成功。