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: 8631185
• 负责人: David L Brody
• 金额: $ 40.76万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631185
• 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; Emotional; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Event; Goals; 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; Regulation; 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; base; clinically relevant; cognitive function; controlled cortical impact; design; fimbria; hyperphosphorylated tau; immunoreactivity; improved; injured; innovation; interest; kinase inhibitor; mood regulation; mouse model; mutant; neurotoxic; new therapeutic target; novel; pre-clinical; prevent; prion-like; public health relevance; research study; small molecule; stress-activated protein kinase 1; tau Proteins; tau aggregation; tau mutation; tau-protein kinase; therapeutic development; therapeutic target; white matter; white matter injury

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 definition 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 an 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.

创伤性脑损伤（TBI）一直是死亡的主要原因，并威胁到整个人类的最佳脑功能。 人类存在的历史。可以逆转或预防的延迟继发性损伤过程很重要 TBI的治疗目标。该项目的重点是涉及tau蛋白的继发性损伤过程。异常 在许多TBI患者的脑中，在损伤后数小时至数天检测到tau的聚集。Tau可能参与了 在类似于阿尔茨海默病的痴呆症的早期发展中，tau蛋白是慢性创伤性痴呆症的标志。 在患有TBI的拳击手、足球运动员和军事人员中观察到的脑病。重要的是，最新的定义 tau蛋白病理学谱现在不仅包括在显微镜下可见的tau蛋白，而且包括小的tau蛋白簇。 称为寡聚体和聚集形式的tau蛋白，可以通过触发额外的tau蛋白聚集在大脑中传播。 然而，TBI后tau病理学的潜在机制尚不清楚，这在很大程度上是由于缺乏直到 最近的一个适当的小动物模型。为了解决这个问题，我们开发了第一个转基因小鼠模型， 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，我们现在建议测试 假设tau寡聚体和扩散的tau聚集有助于TBI后延迟的脑变性。 这些研究将与德克萨斯大学加尔维斯顿分校的Rakez Kayed博士和加尔维斯顿分校的Rakez Kayed博士合作进行。 华盛顿大学的马克·戴蒙德和两名研究人员致力于tau生物学的前沿研究。2)有趣的是， 在损伤前用c-jun N-末端激酶（JNK）抑制剂治疗可减少TBI相关的tau蛋白 大脑的病理学对于我们的第二个目标，我们建议测试JNK抑制剂治疗是否在治疗上有效。 损伤后的实际时间阻断了tau病理学并改善了小鼠的结果。我们将评估短期和 长期的病理和行为结果，包括社会行为和情绪调节的创新测试， 小鼠3)在大脑中有三种类型的JNK，称为JNK 1，JNK 2和JNK 3。没有JNK 1或JNK 2的小鼠 免疫系统功能的问题，而没有JNK 3的小鼠实际上受到其他类型大脑的保护 侮辱。我们的假设是JNK 3正在发挥关键作用，并且JNK 3将成为新的更好、更安全的目标 非选择性JNK抑制剂。我们的第三个目标是创造反义寡核苷酸 特异性针对每种JNK。我们将用这些反义寡核苷酸治疗小鼠， 这减少了tau病理学并改善了TBI后的结果。这些反义寡核苷酸有潜力， 因为已经有两种反义治疗剂被批准，大约有35种以上的反义治疗剂被批准用于人类TBI患者。 人体临床试验的各个阶段。我们的合作者，T. M.博士华盛顿大学的米勒和埃里克·斯威兹博士 伊希斯制药公司是世界上反义治疗的专家之一。广泛的长期目标是揭示 导致涉及tau蛋白的继发性损伤过程的机制，并开发治疗方法来阻断它们， 希望这能改善TBI后的结果。全世界对患有tau的运动员和军事人员的兴趣 病理学和慢性创伤性脑病突出了这一调查的紧迫性。