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Delayed and Progressive Emergence of CTE- and Psychiatric-like Pathologies after Repetitive Mild TBI

重复轻度 TBI 后 CTE 和精神病样病理的延迟和进行性出现

基本信息

批准号：
10044414
负责人：
Donald M Kuhn
金额：
--
依托单位：
JOHN D DINGELL VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044414
关键词：
Ablation Acetylation Acute Afghanistan Anxiety Appearance Astrocytes Autopsy Behavior Disorders Behavioral Brain CSF1R gene Chronic Clinical Clinical Trials Cognitive deficits Complex Craniocerebral Trauma Data Deacetylation Depression and Suicide Development Disease Enzymes Equilibrium Exposure to Frequencies Functional disorder Gliosis Goals HDAC6 gene Head Health Healthcare Histone Deacetylase Inhibitor Human Impaired cognition Individual Inflammation Injury Iraq Lead Long-Term Effects Macrophage Colony-Stimulating Factor Receptor Medical Mental Depression Mental disorders Microglia Microtubule Stabilization Military Personnel Mission Modeling Modification Motion Mus Nature Nerve Degeneration Neurological outcome Neurons Outcome Parkinson Disease Pathologic Pathology Phosphorylation Prevention Publishing Research Seeds Sleep Sleep Disorders Symptoms TBI treatment Tauopathies Testing Therapeutic Intervention Time Traumatic Brain Injury Veterans Vision Work base behavioral outcome chronic traumatic encephalopathy clinically significant combat zone comorbidity cost effective therapy experimental study head impact humanized mouse inhibitor/antagonist mild traumatic brain injury military service military veteran mouse model neuroinflammation neuropathology novel novel therapeutics outcome forecast prevent service member tau Proteins tau phosphorylation tau-1 treatment duration virtual white matter

项目摘要

Project Summary/Abstract Traumatic brain injury (TBI) has been referred to as the “signature injury” of recent military combat operations in Iraq and Afghanistan. The form of TBI that is most prevalent among military service members and Veterans is repetitive, mild TBI, or rmTBI. Apart from the immediate effects of a head injury, rmTBI is also associated with a number of significant and chronic co-morbid conditions including cognitive dysfunction, sleep disorders, alterations in visual function, and psychiatric complications (e.g., depression, suicide, anxiety). rmTBI and its co-morbid conditions exact a steep toll on military personnel and Veterans and the cost to the nation of TBI is estimated to be $60 billion annually. The mechanisms by which rmTBI alters brain function are not well understood and all clinical trials of new therapies for TBI thus far have failed. Therefore, an effective treatment for TBI does not exist. Perhaps the most alarming aspect of rmTBI is the possibility that repeated mild impacts to the head do not cause clinically significant or recognizable symptoms but set in motion a cascade which has an endpoint of neurodegeneration and psychiatric illness. The primary goals of this application are to 1) refine and validate a humanized mouse model of rmTBI and 2) test two new mechanism-based therapies for the long-term consequences of rmTBI. These goals will be achieved by employing a new model of rmTBI that is very mild, even after as many as 20 head impacts, and which does not result in any behavioral or neuronal pathology at the end of the treatment period. We include preliminary data showing that rmTBI results in a delayed and progressive emergence of increased reactive gliosis and inflammation along white matter tracts, and increases in the pathologic form of tau, a microtubule stabilizing molecule. In addition, this model of rmTBI results in slowly developing cognitive deficits and psychiatric-like disorders (e.g., anxiety and depression), neither of which are evident immediately after the rmTBI course of treatment. These neuronal and behavioral outcomes are hallmark signs of chronic traumatic encephalopathy (CTE) and have been observed in postmortem brains of military service members exposed to rmTBI. Two new drugs will be tested as therapies for rmTBI and include an inhibitor of histone deacetylase 6 (HDAC6) and a colony-stimulating factor 1 receptor (CSFR1) inhibitor that ablates CNS microglia. The rationale behind the use of an HDAC6 inhibitor for treating rmTBI is compelling for several reasons. First, modification of tau by acetylation protects it from aggregation (i.e., its pathological form) by inhibiting its phosphorylation. Second, HDAC6 has been identified as the specific enzyme that deacetylates tau. Deacetylation of tau allows for modification of tau by phosphorylation. Third, inhibition of HDAC6 should shift the balance of acetylation/phosphorylation to favor acetylation and thereby protect tau against pathological aggregation in brain. The rationale behind the use of a CSF1R inhibitor is likewise compelling and strong because rmTBI results in significant increases in microglial activation which then causes a secondary activation of astrocytes. This increased glial reactivity results in neuronal damage. By ablating microglia, a CSF1R inhibitor should prevent activation of both microglia and astrocytes and reduce the CTE-like damage that occurs in CTE. The effects of rmTBI will be studied over a chronic time-frame in mice to simulate the slow-developing neuropathologies and behavioral disorders seen in humans after repeated head injuries. Treatment will not begin until after exposure of mice to repetitive head impacts in order to simulate a clinical situation more closely. It is hypothesized that inhibition of HDAC6 or CSF1R after rmTBI will prevent or reduce the development of CTE-like tau pathology. It is hypothesized further that prevention of the formation of tauopathies with these treatments will reduce the chronic co-morbid conditions that develop with high frequency after rmTBI to include cognitive dysfunction, alterations in vision and sleep, and depression- and anxiety-like behavioral disorders. This project has high translational relevance for the VA health care mission.

项目总结/文摘