Identification of biomarkers for biochemical, pathophysiological and neurological effects of high ammonia concentration on the central nervous system in a preclinical model of neonatal hyperammonemia
在新生儿高氨血症临床前模型中鉴定高氨浓度对中枢神经系统生化、病理生理学和神经学影响的生物标志物
基本信息
- 批准号:10302593
- 负责人:
- 金额:$ 26.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-18 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAffectAmmoniaAnimal ModelAnimalsArgininosuccinate lyase deficiencyAstrocytesBiochemicalBiological MarkersBiotinidase DeficiencyBloodBrainBrain EdemaBrain InjuriesCellsCessation of lifeChemicalsChronologyCitrullineCitrullinemiaComaComplementCultured CellsDataDevelopmentDiseaseElectroencephalographyEpilepsyExposure toFrequenciesFunctional disorderGlutamatesGlutamineGoalsHolocarboxylase Synthetase DeficiencyHumanHyperammonemiaHyperargininemiaHypoxiaImpairmentInfantIntellectual functioning disabilityKnock-outKnockout MiceLeadLigaseLiverLong-Term EffectsMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMaple Syrup Urine DiseaseMeasuresMetabolismMethodsModelingMolecularMonitorMusN acetyl L glutamateN-carbamylglutamateNeonatalNeonatal Brain InjuryNeuraxisNeurocognitive DeficitNeurologicNeurologic EffectNeuron-Specific EnolaseNewborn AnimalsOrganOrnithine CarbamoyltransferaseOutcomePatient-Focused OutcomesPatientsPatternPharmaceutical PreparationsPharmacotherapyPhenotypePre-Clinical ModelPreclinical TestingProtonsRecoveryResourcesRiskSeizuresSerumSeveritiesSignal TransductionStressSupplementationSymptomsTestingToxic effectTransplant RecipientsUnited States Health Resources and Services AdministrationValidationWaterWithdrawalZebrafishawakebasebiomarker identificationbrain abnormalitiesbrain electrical activitydrug testingexperienceexperimental studyfatty acid oxidationimaging studyimproved outcomeinjury recoveryinsightliver transplantationmature animalneonatal brainneonatal miceneonateneuroprotectionneurotoxicitynovelnovel therapeuticspostnatalpreclinical evaluationpreventresearch clinical testingscreening paneltherapeutically effectivetwo photon microscopy
项目摘要
Abstract
Neonatal hyperammonemia (HA) from any cause, including several screenable disorders, results in brain injury
leading to irreversible intellectual and developmental disabilities, and even death. Current therapies for HA are
targeted at reducing blood ammonia levels; although they can prevent death from brain edema, they are
inefficient at reducing or preventing brain damage. Our understanding of the mechanism of ammonia toxicity to
the brain is based on experiments in cultured cells and adult animal models; HA disrupts glutamine, glutamate,
and K+ metabolism in the astrocytes leading to osmotic stress and brain edema. However, it is not known how
HA affects the developing brain because animal models suitable for studying molecular, biochemical,
pathophysiological, and neurological effects of HA on the neonatal brain currently do not exist. We have
created an animal model of inducible HA, the N-acetylglutamate synthase knockout (NAGSko) mouse.
Homozygous knockout mice survive into adulthood and reproduces when treated with N-carbamylglutamate and
citrulline, and develop HA when treatment is stopped. We propose to use the NAGSko mice as a model of
inducible neonatal HA. Our goal is to establish biomarkers of HA that could be used in both preclinical and clinical
testing of neuroprotection drugs. Our specific aims are: 1. To induce HA in neonatal NAGSko mice and determine
whether associated MRS biochemical changes in their brains persist after ureagenesis has been normalized.
We will induce HA in NAGSko mice at postnatal day 13 (P13) and measure metabolite differences in the brains
of HA NAGSko mice and non-HA littermates during HA episode and 2 weeks post recovery from HA. Brain
metabolites will be measured using proton magnetic resonance spectroscopy (1H-MRS). 2. To determine
whether neonatal HA episode causes persistent abnormal astrocyte function that correlates with blood
biomarkers of brain damage. We will use our novel NAGSko/ALDH1L1/GCamp5G-tdTm mice and 2-photon
microscopy to monitor changes in Ca2+ signaling during neonatal HA episode and its long-term consequences
on astrocytic Ca2+ signaling in awake animals, Changes in Ca2+ signaling will be correlated to serum biomarkers
of brain injury S100B and NSE (neuron-specific enolase). 3. To determine whether neonatal HA episode causes
persistent abnormal brain electrical activity. We will assess whether a neonatal HA episode increases frequency
and severity of seizures after normalization of ureagenesis in the NAGSko mice. After validation, we plan to use
EEG patterns, 1H-MRS and blood biomarkers of brain damage as biomarkers of HA in pre-clinical and clinical
evaluation of drugs and therapies for the protection of the brain from ammonia toxicity. If successful, drugs
that result from these trials will complement current treatment approaches and improve the outcome of
patients with HA.
摘要
任何原因引起的新生儿高氨血症(HA),包括几种可筛查的疾病,都会导致脑损伤
导致不可逆转的智力和发育障碍,甚至死亡。目前治疗HA的方法有
旨在降低血氨水平;尽管它们可以防止死于脑水肿,但它们
在减少或预防脑损伤方面效率低下。我们对氨中毒机制的认识
大脑基于培养细胞和成年动物模型的实验;HA破坏谷氨酰胺,谷氨酸,
星形胶质细胞的K+代谢导致渗透应激和脑水肿。然而,目前还不知道是如何
HA影响发育中的大脑,因为动物模型适合研究分子、生化、
目前尚不存在HA对新生儿大脑的病理生理和神经学影响。我们有
建立了诱导性HA的动物模型,N-乙酰谷氨酸合成酶基因敲除(NAGSko)小鼠。
纯合子基因敲除小鼠在N-氨基甲酰谷氨酸和N-氨基甲酰谷氨酸处理后存活并繁殖
瓜氨酸,并在治疗停止时产生HA。我们建议使用NAGSko小鼠作为一种
可诱导的新生儿HA。我们的目标是建立可用于临床前和临床的HA生物标记物
神经保护药物的测试。我们的具体目标是:1.诱导新生NAGSko小鼠HA并测定
在尿失禁正常化后,他们大脑中相关的MRS生化变化是否会持续下去。
我们将在出生后第13天(P13)在NAGSko小鼠体内诱导HA,并测量大脑中代谢物的差异
在HA发病期间和从HA中恢复2周后,观察HA NAGSko小鼠和非HA仔鼠的情况。脑区
代谢物将使用质子磁共振波谱(1H-MRS)进行测量。2.确定
新生儿HA事件是否导致持续性星形胶质细胞功能异常与血液相关
脑损伤的生物标志物。我们将使用我们的新型NAGSko/ALDH1L1/GCamp5G-TDTM小鼠和双光子
显微镜监测新生儿HA发病过程中钙信号的变化及其长期后果
清醒动物星形胶质细胞钙信号的变化将与血清生物标志物相关
脑损伤的S100B和NSE(神经元特异性烯醇化酶)。3.确定新生儿HA发病是否导致
持续异常的脑电活动。我们将评估新生儿HA发作是否会增加频率
以及NAGSko小鼠尿失禁正常化后癫痫发作的严重程度。经过验证后,我们计划使用
脑电图型、1H-MRS和脑损伤的血液生物标志物作为HA的临床前和临床生物标志物
保护大脑免受氨中毒影响的药物和治疗方法的评价。如果成功,药物
这些试验的结果将补充目前的治疗方法,并改善
患有HA的患者。
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 }}
Nicholas Ah Mew其他文献
Nicholas Ah Mew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('Nicholas Ah Mew', 18)}}的其他基金
Expert curation of sequence variants in the proximal urea cycle genes
近端尿素循环基因序列变异的专家管理
- 批准号:
10630560 - 财政年份:2023
- 资助金额:
$ 26.78万 - 项目类别:
Identification of biomarkers for biochemical, pathophysiological and neurological effects of high ammonia concentration on the central nervous system in a preclinical model of neonatal hyperammonemia
在新生儿高氨血症临床前模型中鉴定高氨浓度对中枢神经系统生化、病理生理学和神经学影响的生物标志物
- 批准号:
10490324 - 财政年份:2021
- 资助金额:
$ 26.78万 - 项目类别:
Systemic biomarkers of brain injury from hyperammonemia
高氨血症脑损伤的全身生物标志物
- 批准号:
10015370 - 财政年份:2019
- 资助金额:
$ 26.78万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 26.78万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 26.78万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 26.78万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 26.78万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 26.78万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 26.78万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 26.78万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 26.78万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 26.78万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 26.78万 - 项目类别:
Grant-in-Aid for Scientific Research (C)