Optimizing Heme Oxygenase Activity after CNS Hemorrhage
中枢神经系统出血后优化血红素加氧酶活性
基本信息
- 批准号:7340719
- 负责人:
- 金额:$ 23.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-01-01 至 2009-12-31
- 项目状态:已结题
- 来源:
- 关键词:ALPPAccountingAdenovirus VectorAdenovirusesAffectAstrocytesAttenuatedAutologousBloodBlood ClotBlood coagulationBrain InjuriesBrain hemorrhageCell DeathCell SurvivalCerebral hemisphere hemorrhageChelating AgentsCoagulation ProcessCorpus striatum structureCraniocerebral TraumaCytolysisDevelopmentDiseaseDrug Delivery SystemsEdemaEnzyme GeneEnzyme Inhibitor DrugsEnzyme InhibitorsEnzymesErythrocytesGF109203XGene DeletionGene TransferGenesGenetic TranscriptionGlial Fibrillary Acidic ProteinGoalsHematomaHemeHeminHemoglobinHemorrhageHourHumanImmunoblottingImmunohistochemistryInjection of therapeutic agentInjuryIronIschemiaIschemic StrokeLaboratoriesLate EffectsLeadLesionLifeLipid PeroxidationLipidsMediatingMorbidity - disease rateMusNeurogliaNeurologicNeuronsOxidative StressOxygenasesPathway interactionsPhosphorylationPhosphotransferasesPrevalenceProcessProtein IsoformsProtein Kinase C InhibitorProteinsReactive Oxygen SpeciesRecombinantsRegulationResearch PersonnelResistanceSiteStaining methodStainsStrokeSubarachnoid HemorrhageSurvivorsSynapsinsTherapeutic InterventionThrombinTimeTissuesToxic effectTraumaTraumatic CNS injuryVirus Diseasesbenzotriazolecell typedesignenzyme activitygene therapyheme oxygenase-1heme oxygenase-2improvedinhibitor/antagonistinjuredintraperitonealmortalityneurotoxicityoxidationpreventprogramspromotertherapeutic targettreatment effectvector
项目摘要
Intracerebral hemorrhage accompanies most CNS traumatic injuries and about 15% of strokes. Increasing
9vidence suggests that hemoglobin (Hb) release from lysing erythrocytes may contribute to oxidative stress
n surrounding tissue. Because of its prolonged time course, Hb toxicity may be an ideal target for
therapeutic intervention. Prior studies have demonstrated that Hb affects the survival of neurons and
astrocytes by pathways that are largely dependent on the heme oxygenase enzymes (HO). HO-1 is
inducible, and is found primarily in glia, where it is protective; HO-2 is expressed mainly in neurons, where it
worsens injury. Unfortunately, HO inhibitors block both isoforms, and increase injury to astrocytes while
protecting neurons. The goal of this project is to develop a strategy that will optimize HO activity in both cell
types after hemorrhage. We hypothesize that this may be accomplished by two approaches: 1) exploiting
differences in the regulation of HO-1 and HO-2 activation; 2) transferring sense and antisense HO genes
with promoters that target transcription to specific cell types. Our experimental aims are as follows: 1)
Decrease neuronal HO-2 activity in cortical cultures by inhibiting its activation by CK2, using specific
benzotriazole inhibitors. Determine the effect of this treatment on culture HO activity, reactive oxygen
species (ROS) formation, and cell viability after Hb or hemin exposure. 2) Construct an adenovirus encoding
the HO-1 gene driven by the astrocyte-specific GFAP promoter. Quantify its expression in astrocytes and
neurons, and determine its effect on heme-mediated ROS formation and cell death. 3) Construct an
adenovirus containing the HO-2 gene in antisense orientation, driven by the neuron-specific synapsin-1
promoter. Quantify its effect on HO-2 expression in cultured astrocytes and neurons, and on heme-mediated
oxidative injury. 4) Stereotactically inject blood into the striata of mice, alone or with sense HO-1, antisense
HO-2, or both vectors. Alternatively, treat blood-injected mice with intraperitoneal CK2 inhibitors. At 72 and
144 hours, determine the effect on lesion volume using TTC staining. Quantify cellular protein and lipid
oxidation in surrounding tissue. The information gained in this project may lead to new treatments for victims
of hemorrhagic stroke and head trauma. The ultimate goal is to reduce brain injury in tissue surrounding a
blood clot, and to thereby improve the likelihood of survival and return to an independent, productive life.
脑出血伴发大多数中枢神经系统损伤和约15%的卒中。渐增
证据表明,溶解的红细胞释放的血红蛋白可能与氧化应激有关
N周围组织。由于其较长的时间进程,Hb毒性可能是
治疗性干预。先前的研究表明,Hb影响神经元的存活和
星形胶质细胞通过在很大程度上依赖于血红素加氧酶(HO)的途径。HO-1是
HO-2主要在神经细胞中表达,在那里它是有保护作用的。
会加重伤势。不幸的是,HO抑制剂阻断了这两种异构体,并增加了对星形胶质细胞的损伤
保护神经元。这个项目的目标是开发一种策略,优化两个细胞中的HO活性
出血后分型。我们假设这可以通过两种方法来实现:1)利用
HO-1和HO-2激活调控的差异;2)转导正义和反义HO基因
带有针对特定细胞类型的转录的启动子。我们的实验目标如下:1)
通过抑制CK2的激活来降低皮质培养中神经元HO-2的活性
苯并三氮唑类抑制剂。确定该处理对培养物HO活性、活性氧
在Hb或氯化血红素暴露后,物种(ROS)的形成和细胞活力。2)构建编码基因的腺病毒
HO-1基因由星形胶质细胞特异性GFAP启动子驱动。量化其在星形胶质细胞中的表达
并确定其在血红素介导的ROS形成和细胞死亡中的作用。3)构建一个
神经元特异性突触素-1驱动的反义定向携带HO-2基因的腺病毒
推动者。量化其对培养的星形胶质细胞和神经元HO-2表达的影响以及对血红素介导的影响
氧化损伤。4)单独或联合正义HO-1、反义HO-1向小鼠纹状体内立体定向注射血液
HO-2,或两个载体。或者,用CK2抑制剂治疗注射血液的小鼠。年满72岁,
144小时,用TTC染色确定对病变体积的影响。细胞蛋白质和脂肪的定量
周围组织的氧化作用。从这个项目中获得的信息可能会为受害者带来新的治疗方法
出血性中风和头部创伤。最终目标是减少脑部周围组织的损伤。
减少血液凝块,从而提高生存的可能性,并恢复独立的、富有成效的生活。
项目成果
期刊论文数量(0)
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{{ truncateString('RAYMOND F REGAN', 18)}}的其他基金
Protective effect of astrocyte heme oxygenase-1 after intracerebral hemorrhage
星形胶质细胞血红素氧合酶1对脑出血后的保护作用
- 批准号:
9914357 - 财政年份:2018
- 资助金额:
$ 23.7万 - 项目类别:
Effect of Hemopexin Therapy after Intracerebral Hemorrhage
血红素结合蛋白治疗脑出血后的效果
- 批准号:
8969426 - 财政年份:2015
- 资助金额:
$ 23.7万 - 项目类别:
Protective Effect of Hemin Preconditioning after Intracerebral Hemorrhage
氯化血红素预处理对脑出血后的保护作用
- 批准号:
8847812 - 财政年份:2012
- 资助金额:
$ 23.7万 - 项目类别:
Protective Effect of Hemin Preconditioning after Intracerebral Hemorrhage
氯化血红素预处理对脑出血后的保护作用
- 批准号:
8346310 - 财政年份:2012
- 资助金额:
$ 23.7万 - 项目类别:
Protective Effect of Hemin Preconditioning after Intracerebral Hemorrhage
氯化血红素预处理对脑出血后的保护作用
- 批准号:
8472555 - 财政年份:2012
- 资助金额:
$ 23.7万 - 项目类别:
Protective Effect of Hemin Preconditioning after Intracerebral Hemorrhage
氯化血红素预处理对脑出血后的保护作用
- 批准号:
8661320 - 财政年份:2012
- 资助金额:
$ 23.7万 - 项目类别:
A fluorescent method to quantify neuronal injury after intracerebral hemorrhage
定量脑出血后神经元损伤的荧光方法
- 批准号:
8191650 - 财政年份:2011
- 资助金额:
$ 23.7万 - 项目类别:
A fluorescent method to quantify neuronal injury after intracerebral hemorrhage
定量脑出血后神经元损伤的荧光方法
- 批准号:
8290451 - 财政年份:2011
- 资助金额:
$ 23.7万 - 项目类别:
Optimizing Heme Oxygenase Activity after CNS Hemorrhage
中枢神经系统出血后优化血红素加氧酶活性
- 批准号:
7046350 - 财政年份:2006
- 资助金额:
$ 23.7万 - 项目类别:
Optimizing Heme Oxygenase Activity after CNS Hemorrhage
中枢神经系统出血后优化血红素加氧酶活性
- 批准号:
7162512 - 财政年份:2006
- 资助金额:
$ 23.7万 - 项目类别:
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