NICOTINAMIDE MONONUCLEOTIDE ADENYLYLTRANSFERASES IN NEONATAL HYPOXIA-ISCHEMIA
烟酰胺单核苷酸腺苷酸转移酶在新生儿缺氧缺血中的作用
基本信息
- 批准号:8692037
- 负责人:
- 金额:$ 17.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcuteAffectAnimal ModelAnimalsAxonBiochemicalBiological ProcessBrainBrain Hypoxia-IschemiaBrain InjuriesBrain regionBuffersCalciumCause of DeathCell DeathCellsCerebral PalsyCessation of lifeChronicClinicalDevelopmentDiseaseEnzymesEpilepsyFamilyFluorescent DyesFunctional disorderGene ExpressionGenesGenetic TechniquesGlutamate ReceptorGlutamatesGoalsHigh PrevalenceHomologous GeneHumanHypoxiaInjuryIntellectual functioning disabilityInterventionK-Series Research Career ProgramsKnock-outKnowledgeLaboratoriesLeadLeber&aposs amaurosisLightMediatingMembrane PotentialsMentorsMentorshipMethodsMitochondriaModelingMolecular GeneticsMutationNeonatalNeonatal Brain InjuryNerve DegenerationNeuraxisNeurobiologyNeurodegenerative DisordersNeurologicNeuronsNewborn InfantNicotinamide adenine dinucleotideNicotinamide-Nucleotide AdenylyltransferasePathway interactionsPatternPerinatalPeripheralPeripheral NervesPhysiciansPhysiologyPlayPreventionPrevention strategyProcessPropertyProteinsReceptor ActivationRegulationRetinaRoleScientistSystemTechniquesTestingTimeTransduction GeneTransgenic AnimalsTransgenic ModelViralWestern Blottingbaseeffective therapyexcitotoxicityin vitro Modelin vivoinjuredknock-downmitochondrial membranemouse modelneonatal hypoxic-ischemic brain injuryneonatenerve injurynervous system disorderneurobiological mechanismneuron lossneuronal survivalneuroprotectionnew therapeutic targetnovel therapeuticsoverexpressionpublic health relevanceresearch studyvector
项目摘要
DESCRIPTION (provided by applicant): The goal of this Mentored Career Development Award is to facilitate Dr. Rafael Galindo's transition to independence as a physician-scientist studying the neurobiological mechanisms of neuronal death in injured developing neurons. The proposed experiments will be conducted under the mentorship of Dr. David Holtzman, and they will examine the potential neuroprotective role of a family of three NAD+ metabolizing enzymes, known as nicotinamide mononucleotide adenylyltransferases (NMNATs), in neonatal brain hypoxia- ischemia (H-I). This form of injury is the most common cause of death in the newborn period and accounts for a significant portion of the chronic neurological conditions attributed to brain injury in the perinatal period. Despite its high prevalence, there are only limited effective
therapies available for newborns exposed to H-I. This lack of effective clinical intervention is attributed, in part, to our incomplete understanding of the neurobiological mechanisms and molecules that regulate neuronal death pathways in the healthy and injured developing brain. NMNATs are molecules that have been shown to have strong neuroprotective properties and are likely importantly involved in the neurodegenerative mechanisms of various central and peripheral neurological diseases. Nevertheless, the neuroprotective properties of NMNATs in the central nervous system have not yet been well studied, and its potential role in the injured and healthy immature brain is even less well understood. The goal of this project is to test the hypothesis that endogenous and exogenous NMNAT proteins protect developing neurons from the effects of H-I by increasing the calcium buffering capacity of mitochondria. In order to test this hypothesis, this proposal will utilized various biochemical, immunological, molecular and genetic techniques to assess the role of these proteins in injured developing neurons through the following aims: 1) To characterize the expression and role of endogenous NMNATs in cell death following neonatal H-I utilizing immunochemical and bimolecular methods of NMNAT gene expression and employing gene knock-down techniques. 2) To assess the neuroprotective role of exogenous NMNAT 1, 2 and 3 in the neonatal brain following H-I using transgenic animal models and gene transduction systems. 3) Investigate the neuroprotective mechanism of NMNAT(s) in the neonatal brain employing biochemical and bioluminescent techniques to examine mitochondrial physiology in over- and under-expressing NMNAT in vitro models of H-I and excitotoxicity. The proposed experiments will likely shed new light in our understanding of the biological processes that regulate neuronal cell death in the developing newborn brain. Furthermore, this knowledge may ultimately lead to identifying novel therapeutic targets for the treatment and prevention of the neurological consequences attributed to brain injury in the newborn.
描述(由申请者提供):这个指导职业发展奖的目标是促进Rafael Galindo博士向独立的过渡,他是一名内科科学家,研究受损的发育中神经元中神经元死亡的神经生物学机制。拟议中的实验将在David Holtzman博士的指导下进行,他们将研究三种NAD+代谢酶家族,即烟酰胺单核苷酸腺基转移酶(NMNats)在新生儿脑缺氧缺血(H-I)中的潜在神经保护作用。这种形式的损伤是新生儿期最常见的死亡原因,占围产期脑损伤所致慢性神经疾病的很大一部分。尽管它的流行率很高,但只有有限的有效
暴露于H-I的新生儿可采用的治疗方法。缺乏有效的临床干预部分归因于我们对调节健康和受损发育中大脑神经元死亡途径的神经生物学机制和分子的不完全了解。NMNAs是已被证明具有强大的神经保护特性的分子,可能在各种中枢和外周神经疾病的神经退行性机制中发挥重要作用。然而,NMNAs在中枢神经系统中的神经保护作用尚未得到很好的研究,其在受损和健康的未成熟脑中的潜在作用更是知之甚少。该项目的目的是验证内源性和外源性NMNAT蛋白通过增加线粒体的钙缓冲能力来保护发育中的神经元免受缺氧影响的假说。为了验证这一假说,本研究将利用不同的生化、免疫学、分子和遗传学技术,通过以下目的来评估这些蛋白在受损发育中神经元中的作用:1)利用免疫化学和双分子方法检测NMNAT基因的表达,并采用基因敲除技术来表征内源性NMNAT在新生儿H-I后细胞死亡中的表达和作用。2)利用转基因动物模型和基因转导系统评价外源性NMNAT 1、2和3在新生大鼠脑缺血后的神经保护作用。3)应用生化和生物发光技术检测新生大鼠缺氧缺血和兴奋性毒性模型中高表达和低表达的脑线粒体生理学变化,探讨S对新生大鼠的神经保护作用机制。拟议中的实验可能会为我们理解调节发育中的新生儿大脑神经细胞死亡的生物过程提供新的线索。此外,这一知识可能最终导致确定新的治疗目标,用于治疗和预防新生儿脑损伤所致的神经后果。
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)
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Rafael Galindo其他文献
Rafael Galindo的其他文献
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{{ truncateString('Rafael Galindo', 18)}}的其他基金
Neuroprotective Actions of hCG in a Mouse Model of Term and Preterm Brain Injury
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- 批准号:
10621384 - 财政年份:2019
- 资助金额:
$ 17.28万 - 项目类别:
Neuroprotective Actions of hCG in a Mouse Model of Term and Preterm Brain Injury
hCG 在足月和早产脑损伤小鼠模型中的神经保护作用
- 批准号:
9975241 - 财政年份:2019
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$ 17.28万 - 项目类别:
Neuroprotective Actions of hCG in a Mouse Model of Term and Preterm Brain Injury
hCG 在足月和早产脑损伤小鼠模型中的神经保护作用
- 批准号:
10404106 - 财政年份:2019
- 资助金额:
$ 17.28万 - 项目类别:
Neuroprotective Actions of hCG in a Mouse Model of Term and Preterm Brain Injury
hCG 在足月和早产脑损伤小鼠模型中的神经保护作用
- 批准号:
9797784 - 财政年份:2019
- 资助金额:
$ 17.28万 - 项目类别:
Development of a Neuroprotective Agent For Cerebral Palsy Prevention
开发用于预防脑瘫的神经保护剂
- 批准号:
8714223 - 财政年份:2014
- 资助金额:
$ 17.28万 - 项目类别:
NICOTINAMIDE MONONUCLEOTIDE ADENYLYLTRANSFERASES IN NEONATAL HYPOXIA-ISCHEMIA
烟酰胺单核苷酸腺苷酸转移酶在新生儿缺氧缺血中的作用
- 批准号:
8567767 - 财政年份:2013
- 资助金额:
$ 17.28万 - 项目类别:
NICOTINAMIDE MONONUCLEOTIDE ADENYLYLTRANSFERASES IN NEONATAL HYPOXIA-ISCHEMIA
烟酰胺单核苷酸腺苷酸转移酶在新生儿缺氧缺血中的作用
- 批准号:
8869060 - 财政年份:2013
- 资助金额:
$ 17.28万 - 项目类别:
NICOTINAMIDE MONONUCLEOTIDE ADENYLYLTRANSFERASES IN NEONATAL HYPOXIA-ISCHEMIA
烟酰胺单核苷酸腺苷酸转移酶在新生儿缺氧缺血中的作用
- 批准号:
9091656 - 财政年份:2013
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