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Repetitive mTBI-induced neurobehavioral changes and CTE-like proteinopathy

重复性 mTBI 诱导的神经行为变化和 CTE 样蛋白病

基本信息

批准号：
9911991
负责人：
KEVIN Ka Wang WANG
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911991
关键词：
Address Affect Aggressive behavior Aging Anxiety Autopsy Behavior Biochemical Biological Assay Biological Markers Brain Brain region Chronic Chronic Phase Clinical Research Closed head injuries Cognitive Cognitive deficits Confusion Craniocerebral Trauma DNA-Binding Proteins Data Dementia Deposition Development Diagnosis Enzyme-Linked Immunosorbent Assay Human Immunization Immunoassay Immunotherapeutic agent Immunotherapy Impaired cognition Impairment Injury Knowledge Lead Learning Link MAPT gene Memory Loss Mental Depression Military Personnel Mission Modeling Mus Nerve Degeneration Nervous System Trauma Neurologic Pathologic Patient Care Patients Phase Phosphorylation Prevention Protein Fragment Proteins Research Risk Rodent Serum Symptoms TDP-43 aggregation Testing Time Transgenic Mice Transgenic Organisms Translating Veterans Wild Type Mouse Work base brain tissue chronic traumatic encephalopathy combat depressive symptoms experience extracellular human subject improved link protein mild traumatic brain injury mouse model neurobehavioral neurobehavioral test neuropathology novel overexpression oxidation protein TDP-43 protein aggregation protein biomarkers tau Proteins tau-1 tool

项目摘要

Repetitive mild closed head injury (rCHI) is a common form of mild traumatic brain injury (mTBI) among military personnel in both combat and non-combat missions. rCHI can result in sustained cognitive decline and neurobehavioral changes (such as anxiety and depression-like behaviors) [1]. More recently rCHI has also been linked to the formation of a neurodegenerative condition called chronic traumatic encephalopathy (CTE). CTE is pathologically characterized by protein aggregate deposit found in the cortex and other brain regions, post-mortem. Two major proteins found in these CTE protein deposits are microtubule-associated protein Tau and TAR DNA-binding protein (TDP-43) [2-5]. Patients with CTE may show symptoms of dementia, such as memory loss, confusion, anxiety, depression and aggression, which generally appear years or decade(s) after the occurrence of neurotrauma. The Central Hypothesis to be tested is that chronic cognitive and neurobehavioral changes following repetitive mTBI (rCHI) is closely linked to post-injury Tau and TDP-43 proteinopathy development. In addition, the proposed work will not only allow us to test this hypothesis, but also enable us to validate novel CTE biomarkers tests as well as to examine a novel Tau, TDP-43 proteinopathy-based immunotherapy strategy towards improvement of chronic neurobehavioral deficits. Three specific aims are proposed in this application to address the central hypothesis. In Specific Aim 1, we will subject wildtype mice to repetitive close head injury (rCHI) and follow them from subacute to chronic period (up to 18 mo.) to characterize cognitive and neurobehavioral changes, overall neuropathology and their correlation with time-dependent CTE-like Tau/P-tau and TDP-43 protein accumulation /proteinopathy signatures in brain tissue and biofluid. In Specific Aim 2 we will subject human-tau (hTau) transgenic mice and TDP-43 overexpressing transgenic mice to rCHI and follow them from subacute to chronic period to examine if they develop worsened cognitive and neurobehavioral changes, neuropathology and accelerated, exaggerated Tau/TDP-43 proteinopathy signatures in brain tissue and biofluid. Lastly, in Specific Aim 3, we will combine our learning from rCHI models in Aim 1 & 2 to test potential effects of Tau/P-Tau and TDP-43 immunization as novel immunotherapy for reducing rCHI-induced Tau and TDP-43 proteinopathy load and mitigating chronic cognitive, neurobehavioral and neuropathological changes in wildtype, hTau, TDP-43 transgenic and/or hTau/TDP-43 double transgenic mouse lines. This proposed systemic study will advance our understanding of the neurobehavioral (anxiety, depression, cognitive dysfunctions) and their potential linkage to the biochemical/protein changes of aggregation-prone proteins such as Tau and TDP-43 (proteinopathy) and CTE- like neurodegenerative cascade during the chronic phase of TBI. Such knowledge can translate into the ability for VA to devise better management tools and improved Veteran patient care. Our findings will also help us better diagnose chronic TBI including ultrasensitive biofluid-based Tau/P-tau and TDP-43-biomarker tests. Furthermore our research also points to a novel and promising immunotherapeutic strategy to treat such conditions. Taken together, these are all significant biomedical advances consistent with the research mission of the NF/SG VHS and VA and meet the full intent of the RFA. Importantly, the learning from this rodent studies and the immunotherapy approach can rapidly translate into clinical studies with Veterans who are at risk of developing post-TBI CTE.

重复性轻度闭合性脑损伤（rCHI）是军人中常见的一种轻度创伤性脑损伤形式