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:10255988
- 负责人:
- 金额:$ 47.96万
- 依托单位:
- 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 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationBone MarrowBrainBrain InjuriesCerebrumClinicalCognitiveDevelopmentDoseEmotionalEncephalitisExcisionFemaleFunctional disorderGenderGeneticGenetic TranscriptionHDAC1 geneHDAC2 geneHDAC3 geneHistone DeacetylaseHistone Deacetylase InhibitorHistonesIn VitroInflammationInflammatoryInflammatory ResponseInjuryKnock-outLysineMacrophage ActivationMediatingMediator of activation proteinMicrogliaModelingMolecularMusNervous System PhysiologyNeuronal InjuryNeuronsOutcomePharmacologyPhenotypePilot ProjectsPlayPost-Translational Protein ProcessingProteinsQuality of lifeRecoveryRecovery of FunctionRehabilitation therapyResolutionRoleSTAT1 proteinSensorimotor functionsSignal PathwaySignal TransductionStretchingStructureTamoxifenTestingTherapeuticTimeTissuesTraumatic Brain Injuryagedbrain remodelingbrain repairbrain tissuecognitive functionconditional knockoutcontrolled cortical impactfunctional groupgray matterimprovedin vitro Modelin vivoinhibitor/antagonistinjury and repairmacrophagemalememberneurobehavioralneuroinflammationneuroprotectionneuropsychiatryneurorestorationneurotoxicitynew therapeutic targetnon-histone proteinnovelnovel therapeutic interventionpreservationpreventresponsesexsubcutaneoustherapeutic evaluationtherapeutic targettoolwhite matteryoung 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.
新的证据表明脑炎症在创伤性脑损伤的病理生理学中起着关键作用
创伤(TBI)。TBI后,小胶质细胞/巨噬细胞可能呈现不同的促炎或炎症反应-
分辨表型,分别增强脑损伤或促进脑修复。细胞内
TBI后决定小胶质细胞/巨噬细胞功能表型的分子开关
明白识别这种分子机制可能会揭示新的目标,以调整小胶质细胞/巨噬细胞
向修复性炎症消退表型发展,并改善TBI的长期结局。
组蛋白脱乙酰基酶(HDAC)催化乙酰基从组蛋白和非组蛋白蛋白去除,
从而不仅调节基因转录,而且通过翻译后调节各种蛋白质的活性,
修改.我们和其他人先前的研究表明,I类HDAC(HDAC 1,2,
3,8)减轻脑炎症和改善TBI后的神经功能。但是,必须
阐明不同HDAC亚型的作用,以专注于特定的治疗靶点,
破坏一些HDAC在损伤后脑修复中的有益功能。迄今为止,HDAC亚型
负责预防TBI的人不详。也不知道细胞/分子机制是否
HDAC介导的潜在保护涉及小胶质细胞/巨噬细胞表型的改变。
我们的初步研究首次表明:1)HDAC 3的小胶质细胞/巨噬细胞特异性敲除(mKO),但
而不是HDAC 1或HDAC 2,改善TBI后的神经行为结果。2)HDAC 3 mKO改善灰度,
白色物质的完整性,并减轻TBI后的神经炎症。4)HDAC 3抑制改善促-
在体外TBI模型神经元牵张损伤(NSI)后炎性小胶质细胞介导的神经毒性。第五章)
HDAC 3抑制减少了信号转导和转录激活因子1(STAT 1)的激活,这是一个关键的信号转导和转录激活因子。
介导小胶质细胞/巨噬细胞中促炎反应的分子。6)皮下递送
RGFP 966是一种脑渗透性、强效和特异性HDAC 3抑制剂,可改善炎症和感觉运动
TBI后的赤字鉴于这些观察结果,我们提出了三个具体目标来检验新的假设,
HDAC 3的遗传或药理学消融提供神经保护并改善脑修复,
TBI后的长期结果,通过促进炎症解决小胶质细胞/巨噬细胞反应。
目的1:测试HDAC 3 mKO是否改善了脑缺血后灰质和白色物质的完整性和长期神经功能。
创伤性脑损伤将在两种性别的小鼠中用他莫昔芬诱导的HDAC 3诱导受控皮质撞击(CCI)。
敲除小胶质细胞/巨噬细胞。目的2:测试HDAC 3-STAT 1信号通路的基因敲除
使小胶质细胞/巨噬细胞在TBI后向有益的和炎症消退的表型转变。目标三:
测试特异性HDAC 3抑制剂RGFP 966在缓解炎症和
在两种性别的年轻成年和老年小鼠中改善长期TBI结果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MICHAEL V L BENNETT其他文献
MICHAEL V L BENNETT的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('MICHAEL V L BENNETT', 18)}}的其他基金
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
- 批准号:
10436968 - 财政年份:2018
- 资助金额:
$ 47.96万 - 项目类别:
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
- 批准号:
10665669 - 财政年份:2018
- 资助金额:
$ 47.96万 - 项目类别:
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
- 批准号:
9697888 - 财政年份:2018
- 资助金额:
$ 47.96万 - 项目类别:
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
- 批准号:
9613417 - 财政年份:2018
- 资助金额:
$ 47.96万 - 项目类别:
Molecular Therapies to Promote White Matter Restoration After Traumatic Brain Injury
分子疗法促进脑外伤后白质恢复
- 批准号:
9773237 - 财政年份:2015
- 资助金额:
$ 47.96万 - 项目类别:
Molecular Therapies to Promote White Matter Restoration After Traumatic Brain Injury
分子疗法促进脑外伤后白质恢复
- 批准号:
9017340 - 财政年份:2015
- 资助金额:
$ 47.96万 - 项目类别:
Cx43 Hemichannels: Gating, Modification and Function
Cx43 半通道:门控、修改和功能
- 批准号:
7643110 - 财政年份:2007
- 资助金额:
$ 47.96万 - 项目类别:
Cx43 Hemichannels: Gating, Modification and Function
Cx43 半通道:门控、修改和功能
- 批准号:
7880655 - 财政年份:2007
- 资助金额:
$ 47.96万 - 项目类别:
Cx43 Hemichannels: Gating, Modification and Function
Cx43 半通道:门控、修改和功能
- 批准号:
7319409 - 财政年份:2007
- 资助金额:
$ 47.96万 - 项目类别:
Cx43 Hemichannels: Gating, Modification and Function
Cx43 半通道:门控、修改和功能
- 批准号:
8130598 - 财政年份:2007
- 资助金额:
$ 47.96万 - 项目类别:
相似海外基金
Impact of physical exercise on brain-bone marrow interactions in postmenopausal rats: potential mechanisms preventing menopause-induced hypertension
体育锻炼对绝经后大鼠脑-骨髓相互作用的影响:预防绝经期高血压的潜在机制
- 批准号:
24K20609 - 财政年份:2024
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Brain-bone marrow interaction in stress-induced hypertension and the protective effects of exercise training
应激性高血压中脑-骨髓相互作用及运动训练的保护作用
- 批准号:
19KK0251 - 财政年份:2019
- 资助金额:
$ 47.96万 - 项目类别:
Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
Bone marrow-derived myeloid cells entering the brain via the choroid plexus are involved in neuroinflammatory and neurodegenerative conditions
骨髓来源的骨髓细胞通过脉络丛进入大脑,参与神经炎症和神经退行性疾病
- 批准号:
18K07072 - 财政年份:2018
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Analysis of oxidative stress in the brain in Alzheimer's disease model mice and establishment of bone marrow mesenchymal stem cell therapy
阿尔茨海默病模型小鼠脑氧化应激分析及骨髓间充质干细胞疗法的建立
- 批准号:
17K16388 - 财政年份:2017
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Simultaneous administration of IL-3 and GM-CSF ameliorates ischemic brain injury: interaction between brain and bone marrow.
同时给予 IL-3 和 GM-CSF 可改善缺血性脑损伤:大脑和骨髓之间的相互作用。
- 批准号:
17K16650 - 财政年份:2017
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Treatment methods for cancer cachexia and sarcopenia that target a novel brain - bone marrow axis and bone-marrow-derived cells
针对新型脑-骨髓轴和骨髓衍生细胞的癌症恶病质和肌肉减少症的治疗方法
- 批准号:
16K09249 - 财政年份:2016
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new psychosomatic factor, bone marrow-derived cells, and clarification of the brain-bone marrow axis on eating disorders
新心身因素、骨髓来源细胞的鉴定以及饮食失调的脑-骨髓轴的澄清
- 批准号:
15K08923 - 财政年份:2015
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular basis for regulation of feeding and food-entrained rhythms via brain-bone marrow network
通过脑骨髓网络调节进食和食物夹带节律的分子基础
- 批准号:
15K15040 - 财政年份:2015
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Fundamental analysis of ischemic brain plasticity induced by bone marrow mesenchymal stem cell transplantation
骨髓间充质干细胞移植致缺血性脑可塑性的基础分析
- 批准号:
26462214 - 财政年份:2014
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Role of bone marrow-derived cells in the brain on neurogenic hypertension
大脑中骨髓源性细胞对神经源性高血压的作用
- 批准号:
24591232 - 财政年份:2012
- 资助金额:
$ 47.96万 - 项目类别:
Grant-in-Aid for Scientific Research (C)