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Novel role and mechanisms of histone deacetylases in traumatic brain injury

组蛋白脱乙酰酶在创伤性脑损伤中的新作用和机制

基本信息

批准号：
9613417
负责人：
MICHAEL V L BENNETT
金额：
$ 47.81万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9613417
关键词：
Ablation Bone Marrow Brain Brain Injuries Cerebrum Clinical Cognitive Development Dose Emotional Encephalitis Excision Female Functional disorder Gender Genetic Genetic Transcription HDAC1 gene HDAC2 gene HDAC3 gene Histone Deacetylase Histone Deacetylase Inhibitor Histones In Vitro Inflammation Inflammatory Inflammatory Response Injury Knock-out Lysine Macrophage Activation Mediating Mediator of activation protein Microglia Modeling Molecular Mus Nervous System Physiology Neuronal Injury Neurons Outcome Pharmacology Phenotype Pilot Projects Play Post-Translational Protein Processing Proteins Quality of life Recovery Recovery of Function Rehabilitation therapy Resolution Role STAT1 protein Sensorimotor functions Signal Pathway Signal Transduction Stretching Tamoxifen Testing Therapeutic Time Tissues Traumatic Brain Injury aged brain remodeling brain repair brain tissue cognitive function controlled cortical impact functional group gray matter improved in vitro Model in vivo inhibitor/antagonist injury and repair macrophage male member neurobehavioral neuroinflammation neuroprotection neuropsychiatry neurorestoration neurotoxicity new therapeutic target non-histone protein novel novel therapeutics prevent response sex subcutaneous therapeutic evaluation therapeutic target tool white matter young adult

项目摘要

Emerging evidence implicates a pivotal role of cerebral inflammation in the pathophysiology of traumatic brain injury (TBI). Following TBI, microglia/macrophages may assume distinct pro-inflammatory or inflammation- resolving phenotypes, which potentiate brain injury or facilitate brain repair, respectively. The intracellular molecular switches that determine microglial/macrophage functional phenotypes after TBI are poorly understood. Identifying such molecular mechanisms may reveal novel targets to tune microglia/macrophages toward the reparative inflammation-resolving phenotype and improve long-term TBI outcomes. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from histone and non-histone proteins, thereby regulating not only gene transcription but also the activity of various proteins through post-translational modifications. Previous studies by us and others demonstrate that pan-inhibitors of Class I HDACs (HDAC1, 2, 3, 8) mitigate brain inflammation and improve neurological functions after TBI. However, it is imperative to elucidate the role of different HDAC subtypes, in order to focus on specific therapeutic targets without disrupting the beneficial functions of some HDACs in post-injury brain repair. To date, the HDAC subtype responsible for protection against TBI is unknown. It is also not known if the cellular/molecular mechanisms underlying HDAC inhibitor-afforded protection involve the alteration of microglial/macrophage phenotype. Our pilot studies show for the first time that: 1) Microglia/macrophage-specific knockout (mKO) of HDAC3, but not HDAC1 or HDAC2, improves neurobehavioral outcomes after TBI. 2) HDAC3 mKO improves gray and white matter integrity, and mitigates neuroinflammation after TBI. 4) HDAC3 inhibition ameliorates pro- inflammatory microglia-mediated neurotoxicity after neuronal stretch injury (NSI), an in vitro TBI model. 5) HDAC3 inhibition reduces the activation of signal transducer and activator of transcription 1 (STAT1), a key molecule that mediates pro-inflammatory responses in microglia/macrophages. 6) Subcutaneous delivery of RGFP966, a brain-penetrant, potent, and specific HDAC3 inhibitor, ameliorates inflammation and sensorimotor deficits after TBI. Given these observations, we propose three specific aims to test the novel hypothesis that genetic or pharmacological ablation of HDAC3 provides neuroprotection and improves brain repair and long-term outcomes after TBI by promoting inflammation-resolving microglial/macrophage responses. Aim 1: Test if HDAC3 mKO improves gray and white matter integrity and long-term neurological functions after TBI. Controlled cortical impact (CCI) will be induced in mice of both sexes with tamoxifen-inducible HDAC3 knockout in microglia/macrophages. Aim 2: Test if genetic knockout of the HDAC3-STAT1 signaling pathway shifts microglia/macrophages toward the beneficial and inflammation-resolving phenotype after TBI. Aim 3: Test the therapeutic potential of the specific HDAC3 inhibitor RGFP966 in resolution of inflammation and improvement of long-term TBI outcomes in young adult and aged mice of both genders.

新出现的证据暗示了脑炎症在创伤性脑病理生理中的关键作用