Mechanisms Underlying Tauopathy Following Traumatic Brain Injury

创伤性脑损伤后 Tau 蛋白病的潜在机制

• 批准号: 8870447
• 负责人: David L Brody
• 金额: $ 39.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870447
• 关键词: 3xTg-AD mouse; Acute; Address; Alzheimer' s Disease; Amygdaloid structure; Amyloid beta-Protein; Animal Model; Antisense Oligonucleotides; Antisense RNA; Area; Axon; Behavioral; Biology; Blocking Antibodies; Brain; Cause of Death; Cell Culture System; Cell Culture Techniques; Chronic; Clinical Trials; Collaborations; Contralateral; Data; Dementia; Deposition; Development; Diamond; Dose; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Event; Goals; Health; Hippocampus (Brain); Hour; Human; Immune system; Immunohistochemistry; Infusion procedures; Injection of therapeutic agent; Injury; Interruption; Intraventricular; Investigation; Ipsilateral; Link; MAPK10 gene; MAPK8 gene; MAPK9 gene; Manufactured football; Mediating; Microscope; Military Personnel; Modeling; Monoclonal Antibodies; Mus; N-terminal; Nerve Degeneration; Neurologic; Oligonucleotides; Outcome; Pathology; Patients; Peptides; Pharmacologic Substance; Phosphotransferases; Play; Process; Production; Protein Isoforms; Publications; Recording of previous events; Relative (related person); Reporting; Research Personnel; Risk; Role; Safety; Secondary to; Social Behavior; Specificity; Staging; Structure; Tauopathies; Testing; Texas; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; Treatment Efficacy; Universities; Washington; Work; adverse outcome; axon injury; base; behavioral outcome; chronic traumatic encephalopathy; clinically relevant; cognitive function; controlled cortical impact; design; emotion regulation; fimbria; hyperphosphorylated tau; immunoreactivity; improved; injured; innovation; interest; kinase inhibitor; mood regulation; mouse model; mutant; neurotoxic; new therapeutic target; novel; peptide A; pre-clinical; prevent; prion-like; research study; small molecule; tau Proteins; tau aggregation; tau mutation; tau-protein kinase; therapeutic development; therapeutic target; white matter; white matter injury

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) has been a major cause of death and threat to optimal brain function throughout the entire history of human existence. Delayed secondary injury processes that could be reversed or prevented are important therapeutic targets for TBI. The focus of this project is on secondary injury processes involving the protein tau. Abnormal aggregations of tau have been detected hours to days after injury in the brains of many TBI patients. Tau may be involved in the early development of dementia similar to Alzheimer's disease, and tau is the hallmark of chronic traumatic encephalopathy seen in boxers, football players, and military personnel with TBIs. Importantly, an up-to-date definitio of the spectrum of tau pathology now includes not only tau that is visible under the microscope, but also small clusters of tau called oligomers and aggregated forms of tau that can spread through the brain by triggering additional tau aggregation. However, the mechanisms underlying tau pathologies following TBI are not understood, in large part due to the lack until recently of a appropriate small animal model. To address this, we developed the first transgenic mouse model which recapitulates many aspects of tau pathology following experimental TBI. 1) For our first aim, we now propose to test the hypothesis that tau oligomers and spreading tau aggregation contribute to delayed brain degeneration following TBI. These studies will be performed in collaboration with Dr. Rakez Kayed at the University of Texas, Galveston and Dr. Marc Diamond at Washington University, two researchers working at the cutting edge of tau biology. 2) Intriguingly, treatment with an inhibitor of an enzyme called c-jun N-terminal kinase (JNK) before injury reduced TBI-related tau pathology in the brain. For our second aim, we propose to test whether treatment with a JNK inhibitor at therapeutically realistic times after injury blocks tau pathology and improves outcomes in mice. We will assess both short term and longer-term pathological and behavioral outcomes, including innovative tests of social behavior and mood regulation in mice. 3) There are three types of JNK in the brain called JNK1, JNK2 and JNK3. Mice without JNK1 or JNK2 have problems with immune system function whereas mice without JNK3 are actually protected from other types of brain insults. Our hypothesis is that JNK3 is playing a key role and that JNK3 would make a better and safer target for new therapeutics than nonselective JNK inhibitors. We propose for our third aim to create antisense oligonucleotides specifically targeting each type of JNK. We will treat mice with these antisense oligonucleotides and determine whether this reduces tau pathology and improves outcomes following TBI. These antisense oligonucleotides have the potential to be used in human TBI patients, as there are two antisense therapeutics already approved and approximately 35 more in various stages of human clinical trials. Our collaborators, Dr. T.M. Miller at Washington University and Dr. Eric Swayze of Isis Pharmaceuticals are among the world's experts in antisense treatments. The broad, long term goals are to uncover the mechanisms leading to secondary injury processes involving tau and develop therapeutics to block them, with the hope that this would improve outcomes following TBI. The worldwide interest in athletes and military personnel with tau pathology and chronic traumatic encephalopathy underscores the urgency of this line of investigation.

描述（由申请人提供）：在人类存在的整个历史中，创伤性脑损伤（TBI）一直是死亡和对最佳大脑功能构成威胁的主要原因。可以逆转或预防的延迟性继发性损伤过程是 TBI 的重要治疗目标。该项目的重点是涉及 tau 蛋白的继发性损伤过程。许多 TBI 患者受伤后数小时至数天的大脑中都检测到了 tau 蛋白的异常聚集。 Tau 蛋白可能参与了类似于阿尔茨海默病的痴呆症的早期发展，并且 tau 蛋白是患有 TBI 的拳击手、足球运动员和军事人员中常见的慢性创伤性脑病的标志。重要的是，tau 病理学谱的最新定义不仅包括显微镜下可见的 tau，还包括称为寡聚体的 tau 小簇和 tau 聚集形式，它们可以通过触发额外的 tau 聚集而在大脑中传播。然而，TBI 后 tau 蛋白病理的机制尚不清楚，很大程度上是由于直到最近还缺乏合适的小动物模型。为了解决这个问题，我们开发了第一个转基因小鼠模型，该模型概括了实验性 TBI 后 tau 病理学的许多方面。 1) 对于我们的第一个目标，我们现在建议检验以下假设：tau 寡聚物和扩散的 tau 聚集有助于 TBI 后延迟的脑退化。这些研究将与德克萨斯大学加尔维斯顿分校的 Rakez Kayed 博士和华盛顿大学的 Marc Diamond 博士合作进行，这两位研究人员致力于 tau 生物学的前沿研究。 2) 有趣的是，在受伤前使用一种名为 c-jun N 末端激酶 (JNK) 的酶抑制剂进行治疗可减少大脑中与 TBI 相关的 tau 病理。对于我们的第二个目标，我们建议测试在损伤后的治疗实际时间使用 JNK 抑制剂治疗是否可以阻断 tau 病理并改善小鼠的结果。我们将评估短期和长期的病理和行为结果，包括对小鼠社会行为和情绪调节的创新测试。 3）大脑中存在三种类型的JNK，分别为JNK1、JNK2和JNK3。没有 JNK1 或 JNK2 的小鼠存在免疫系统功能问题，而没有 JNK3 的小鼠实际上可以免受其他类型的脑损伤。我们的假设是 JNK3 发挥着关键作用，并且 JNK3 将成为比非选择性 JNK 抑制剂更好、更安全的新疗法靶标。我们的第三个目标是创建专门针对每种类型 JNK 的反义寡核苷酸。我们将用这些反义寡核苷酸治疗小鼠，并确定这是否会减少 tau 病理学并改善 TBI 后的结果。这些反义寡核苷酸有可能用于人类 TBI 患者，因为有两种反义疗法已经获得批准，还有大约 35 种反义疗法处于不同阶段的人体临床试验中。我们的合作者，T.M. 博士华盛顿大学的米勒和 Isis Pharmaceuticals 的埃里克·斯韦兹博士是世界反义治疗领域的专家。广泛、长期的目标是揭示导致 tau 蛋白继发性损伤过程的机制，并开发阻断这些机制的疗法，希望这能改善 TBI 后的结果。全世界对患有 tau 蛋白病理学和慢性创伤性脑病的运动员和军事人员的兴趣凸显了这一研究的紧迫性。