Mechanisms of G-CSF-Induced Neuroprotection
G-CSF 诱导的神经保护机制
基本信息
- 批准号:7905765
- 负责人:
- 金额:$ 32.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-05 至 2013-07-31
- 项目状态:已结题
- 来源:
- 关键词:Academic Medical CentersAdultAffectAnimal ModelApoptosisApoptoticBiochemicalBiochemistryBiologicalBiologyBirthBlood - brain barrier anatomyBrainBrain EdemaBrain Hypoxia-IschemiaBrain InfarctionBrain InjuriesBrain-Derived Neurotrophic FactorCaringCell DeathCerebral hemisphere hemorrhageCessation of lifeClinicalClinical SciencesCytotoxic ChemotherapyDataDisciplineDoctor of PhilosophyDown-RegulationEdemaEncephalopathiesEnvironmentFamilyFoundationsGoalsGranulocyte Colony-Stimulating FactorGranulocyte Colony-Stimulating Factor ReceptorsGrowthGrowth FactorHealthHealthcareHematopoieticHematopoietic SystemHumanHypoxiaHypoxic Brain DamageImmunohistochemistryInfantInterventionIschemic Brain InjuryJanus kinase 2LabelLeadLearningLimb structureLong-Term EffectsMeasuresMediatingMedicalMedical centerMemoryMetabolismMitochondriaModelingMolecularMorphologyMotorNeonatalNeonatal Brain InjuryNeonatal Intensive Care UnitsNervous System PhysiologyNeuraxisNeurodevelopmental DisabilityNeurologicNeuronsNeutropeniaOutcomePathway interactionsPerinatalPhysiologyPreventionProteinsPsychologyRattusReflex actionResearchResearch PersonnelRiskRotarod Performance TestScientistSensorimotor functionsSensory ProcessSignal PathwaySignal TransductionStat3 proteinStem cellsSurvivorsTestingTherapeuticTimeTissuesTransient Cerebral IschemiaTranslational ResearchTraumatic Brain InjuryUnited StatesUnited States National Institutes of HealthUniversitiesUp-RegulationWaterWestern Blottingbrain tissuecerebral atrophyclinical practiceclinically relevantdesigneffective therapyfootimprovedinsightmature animalmembernatural hypothermianeonatal hypoxic-ischemic brain injuryneonateneurobehavioralneuroprotectionneurosurgerypreventprotective effectpublic health relevanceresearch clinical testingsocioeconomicstranslational neurosciencetreatment strategy
项目摘要
DESCRIPTION (provided by applicant): No effective treatment strategies have yet been developed to prevent or reduce neonatal hypoxic/ischemic (HI) brain damage. Granulocyte-colony stimulating factor (G-CSF), a member of growth factor family, mainly stimulates the proliferation and differentiation of neutrophilic progenitor cells in the hematopoietic system. It has been widely used in clinical practice for the treatment of neutropenia associated with cytotoxic therapy. Recent studies have shown that systemic administration of G-CSF in adult animal models has mediated noteworthy neuroprotective effects in traumatic brain injury, focal transient cerebral ischemia, and intracerebral hemorrhage but its mechanism(s) are not fully elucidated. Whether G-CSF has neuroprotective effects following neonatal hypoxia-ischemia is not known. As a medical scientist and new investigator to the NIH, I have focused on this important question because of its health relevance, nationally and locally. Loma Linda University Medical Center has the largest Neonatal Intensive Care Unit (NICU) in the Western United States. I have bridged basic and clinical science disciplines to assemble an outstanding research team for this project. Our preliminary studies reveal a significant reduction in brain atrophy following systemic administration of G- CSF to an established rat model of neonatal HI and offer insight into mechanism of action. They support our central hypothesis that systemic G-CSF treatment protects the brain against HI-induced apoptosis. To test our main hypothesis, this project is designated to elucidate the impact of G-CSF-mediated neuroprotection on neurobehavioral outcomes, and thereby define its therapeutic potential. Equally important, this project is designed to determine the suppression of cell death mechanisms especially the mitochondrial apoptotic pathways that mediates the protective effects of G-CSF. The neuroprotective effects of G-CSF on neuronal death and brain atrophy will be related to neurobehavioral outcomes (Specific Aim 1). Brain damage will be measured by brain tissue loss, edema formation, blood-brain barrier disruption, brain infarction, and cellular morphological changes. To strengthen the clinical relevance of this project, the long-term effect and mechanisms of G-CSF treatment on sensorimotor functions, memory and learning abilities will be evaluated by a battery of neurological tests. Then G-CSF's underlying mechanism will be investigated in greater depth by measuring its effect on HI-induced activation of signaling pathways especially mitochondrial apoptotic pathways (Specific Aim 2). The apoptotic changes will be studied using biochemical and molecular approaches. Achieving our project goal through these specific aims will lay the foundation for clinical evaluation of systemic G-CSF in NICU neonates for prevention and treatment of brain damage from HI. PUBLIC HEALTH RELEVANCE: No effective treatment strategies have yet been developed to prevent or reduce neonatal hypoxic/ischemic brain damage. Our project goal is to relate G-CSF's protection of neonates from hypoxia/ischemia-induced brain damage to both neurological function and underlying mechanism. Achieving our goal will lay the foundation for clinical evaluation of systemic administration of G-CSF in human neonates for prevention and treatment of brain damage from hypoxia/ischemia.
描述(由申请人提供):尚未制定有效的治疗策略来预防或减少新生儿缺氧/缺血性(HI)脑损伤。生长因子家族成员的粒细胞 - 固体刺激因子(G-CSF)主要刺激造血系统中嗜中性粒细胞细胞的增殖和分化。它已被广泛用于临床实践中,用于治疗与细胞毒性疗法相关的中性粒细胞减少症。最近的研究表明,成人动物模型中G-CSF的全身施用在创伤性脑损伤,局灶性瞬态大脑缺血和脑出血中介导了值得注意的神经保护作用,但其机制尚未完全阐明。尚不清楚G-CSF在新生儿缺氧 - 缺血性缺血后是否具有神经保护作用。作为NIH的医学科学家和新研究者,我一直专注于这个重要的问题,因为它在全国和本地都具有健康相关性。洛马·琳达大学医学中心拥有美国西部最大的新生儿重症监护病房(NICU)。我已经弥合了基础和临床科学学科,以组建一个杰出的研究团队。我们的初步研究揭示了全身对G-CSF进行全身服用对新生儿HI的大鼠模型后的大脑萎缩的显着降低,并提供了对作用机理的洞察力。他们支持我们的中心假设,即系统性G-CSF治疗可保护大脑免受HI诱导的细胞凋亡。为了检验我们的主要假设,该项目被指定为阐明G-CSF介导的神经保护对神经行为结果的影响,从而定义其治疗潜力。同样重要的是,该项目旨在确定细胞死亡机制的抑制,尤其是介导G-CSF保护作用的线粒体凋亡途径。 G-CSF对神经元死亡和脑萎缩的神经保护作用将与神经行为结局有关(特定目标1)。脑损伤将通过脑组织丧失,水肿形成,血脑屏障破坏,脑梗塞和细胞形态学变化来衡量。为了增强该项目的临床相关性,将通过一系列神经系统测试来评估G-CSF处理对感觉运动功能的长期效果和机制。然后,将通过测量其对高诱导的信号通路激活的影响,特别是线粒体凋亡途径(特定的AIM 2),从而更深入地研究G-CSF的基本机制。将使用生化和分子方法研究凋亡变化。通过这些特定目标实现我们的项目目标将为NICU NEONATES中系统性G-CSF的临床评估奠定基础,以预防和治疗HI的脑损伤。公共卫生相关性:尚未制定有效的治疗策略来预防或减少新生儿缺氧/缺血性脑损伤。我们的项目目标是将G-CSF保护新生儿免受缺氧/缺血引起的脑损伤对神经功能和潜在机制的损害。实现我们的目标将为人类新生儿中G-CSF的全身服用临床评估奠定基础,以预防和治疗低氧/缺血的脑损伤。
项目成果
期刊论文数量(0)
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Jiping Tang其他文献
Jiping Tang的其他文献
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