Cholinergic neuron degeneration after HI: New target for delayed therapy of neonatal HI to improve Learning and Memory Deficits
HI 后胆碱能神经元变性:新生儿 HI 延迟治疗改善学习和记忆缺陷的新目标
基本信息
- 批准号:10451058
- 负责人:
- 金额:$ 24.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-15 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultAffectArousalBehavioralBirthBrainBrain InjuriesCaringCell DeathCerebrumChildCognitionCognitiveCold ChainsComplexCore-Binding FactorCorpus striatum structureDataDecision MakingDevelopmentDiscrimination LearningDiseaseDrug TargetingEncephalopathiesErythropoietinExecutive DysfunctionFaceFormulationFunctional disorderFutureHumanHypoxiaImpaired cognitionInfantInjectionsInjuryLearningLifeLongterm Follow-upMagnetic Resonance ImagingMedicalMemoryMemory impairmentModelingMorbidity - disease rateMusNGFR ProteinNeonatalNeonatal Brain InjuryNerve DegenerationNeurodegenerative DisordersNeuronsNeuropsychologyOralOral cavityOutcomePathologicPathologyPatientsPharmaceutical PreparationsPhasePhenotypePremature InfantPropertyProsencephalonRefrigerationResearchResourcesRestReversal LearningRodentSafetySchool-Age PopulationSignal TransductionStreamSurvivorsSystemTestingTherapeuticTimeTreatment EfficacyVisualbasal forebrainbasebrain cellcholinergiccholinergic neuroncognitive disabilitycostdisabilityexecutive functionflexibilityhypoxia neonatorumhypoxic ischemic injuryimprovedinjuredinnovationnatural hypothermianeonatal careneonatal hypoxic-ischemic brain injuryneural networknovelnovel therapeuticspreventreceptorsafety testingsmall moleculetherapeutic targettouchscreen
项目摘要
Hypoxic-ischemic (HI) encephalopathy (HIE), the most frequent cause of acquired brain injury in preterm and
term infants causeslife-long morbidity. As many as 1 million infants/year suffer HIE with therapeutic
hypothermia (TH) affording a strong survival benefit in those with access to TH. Erythropoietin is also proving
effective both alone and with TH. However, both therapies must be started early. Despite significant progress
in neonatal HI injury research, a therapy that is effective beyond the acute phase of the disease and is orally
bioavailable has been elusive. Most babies affected by HIE have no access NICU care, TH, Epo or any other
upcoming therapies within the necessary time frames. A delayed, easily administered therapy for HIE would
change the future for 1 million children each year. Long term follow-up of HIE patients reveals permanent
learning and memory deficits, lack of cognitive flexibility, and executive dysfunction. MRI studies of former
infants with neonatal brain injury reveals degeneration in the cholinergic basal forebrain (cBF), occurring with
learning and memory deficits and poor executive function. The cBF is essential for proper executive function,
cognitive flexibility, learning and memory, arousal, spatial learning, decision-making, modulation of cortical
activity and the default mode network. The cBF is an interesting and novel potential therapeutic target for
neonatal HI because we now show that neonatal HI precipitates cholinergic neuronal degeneration in the cBF
and striatum. These cholinergic neurons enter a degenerative state 1 month after HI in concert with forebrain
injury and prior to time at which we find poor cognitive flexibility in the neonatal HI model. Much is known
about degeneration of cholinergic neurons in adult neurodegenerative diseases. Importantly, cholinergic
neurons have an extended prodromal phase of degeneration prior to cell death that is amenable to therapy,
and a drug targeting cholinergic neurodegeneration is in adult human trials. LM11A-31 is an orally bioavailable
modulator of p75NTr function that suppresses its neurodegenerative properties and enhances its
neuroprotective actions specifically in the cBF. Based on current data, we hypothesize that initiating treatment
with LM11A-31 after neonatal HI will rescue or prevent degeneration of cholinergic neurons in the cBF and
prevent degeneration of cholinergic input to the cortex resulting in improved learning, memory, and cognition.
We address the hypothesis by using a high through-put behavioral touchscreen testing system, that detects
learning and memory deficits, to rapidly determine LM11A-31 efficacy. Our Aims are 1: To assess the effect of
LM11A-31 in the developing mouse brain and its effect on pathology of neonatal HI throughout the brain,
especially in the injured cBF, when given from 4 days to 10 weeks after neonatal HI.
And 2: Determine whether use of LM11A-31 from 4 days-10 weeks after HI improves visual discrimination
and reversal learning tested 3-6 months after HI and whether this correlates with rescue of the cBF.
缺氧缺血性脑病(HIE)是早产儿获得性脑损伤的最常见原因
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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FRANCES J NORTHINGTON其他文献
FRANCES J NORTHINGTON的其他文献
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{{ truncateString('FRANCES J NORTHINGTON', 18)}}的其他基金
Cholinergic neuron degeneration after HI: New target for delayed therapy of neonatal HI to improve Learning and Memory Deficits
HI 后胆碱能神经元变性:新生儿 HI 延迟治疗改善学习和记忆缺陷的新目标
- 批准号:
10550271 - 财政年份:2022
- 资助金额:
$ 24.56万 - 项目类别:
9th Hershey Conference on Developmental Brain Injury
第九届好时发育性脑损伤会议
- 批准号:
8651669 - 财政年份:2013
- 资助金额:
$ 24.56万 - 项目类别:
Mechanisms of Hypothermic Neuroprotection in Neonates
新生儿低温神经保护机制
- 批准号:
8370698 - 财政年份:2012
- 资助金额:
$ 24.56万 - 项目类别:
Mechanisms of Hypothermic Neuroprotection in Neonates
新生儿低温神经保护机制
- 批准号:
8660703 - 财政年份:2012
- 资助金额:
$ 24.56万 - 项目类别:
Mechanisms of Hypothermic Neuroprotection in Neonates
新生儿低温神经保护机制
- 批准号:
8532947 - 财政年份:2012
- 资助金额:
$ 24.56万 - 项目类别:
FAS Death Receptor Activation in Neonatal Brain Injury
新生儿脑损伤中的 FAS 死亡受体激活
- 批准号:
6780243 - 财政年份:2004
- 资助金额:
$ 24.56万 - 项目类别:
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