A "humanized" mouse model of Glut1 deficiency syndrome.
A "humanized" mouse model of Glut1 deficiency syndrome.
批准号:
10506187
负责人:
Umrao Monani
金额:
$16.45万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-08-15 至 2024-07-31
关键词:
AddressAdultAgeAlzheimer&aposs DiseaseAstrocytesBehavioral AssayBlood CirculationBrainBrain InjuriesCarrier ProteinsCellular AssayCerebrumCessation of lifeChildhoodChronicComaComplexConsumptionDevelopmentDiabetes MellitusDiseaseDisease modelEncapsulatedEpilepsyFailureFamilyFunctional disorderFutureGenerationsGenesGlucoseGlucose TransporterHealthHumanImpaired cognitionIndividualIntuitionLightMalignant NeoplasmsMendelian disorderMolecularMovement DisordersMusNeuronsOrganismOutcomePatientsPhenotypePlant RootsRegulationRetinitis PigmentosaRodentSLC2A1 geneSeizuresSyndromeTestingTherapeuticTherapeutic AgentsTranslatingViolenceWeightWorkcerebral microvasculaturedeprivationdisease phenotypeearly childhoodeffective therapyhuman modelhumanized mousein vivo Modelinfancymouse modelnovelpreclinical studytherapeutic evaluationtherapy developmenttool
中文摘要
项目摘要
相对于它的大小,人脑消耗了人体总能量的不成比例的大量
需要。这种能量主要以葡萄糖的形式提供,必须随时可用并供应给
大脑随需应变。如果不这样做,对有机体会产生可怕的后果,导致一种
神经性低血糖,在严重情况下,昏迷和死亡。而慢性疾病的公开后果
神经性低血糖-认知功能障碍-很容易被识别并得到很好的证实,其细胞和分子
相关因素尚未得到充分定义。了解机械细节的一种方法
潜在的大脑能量匮乏是通过研究遗传决定的大脑能量衰竭来实现的
综合症。葡萄糖转运蛋白-1缺乏综合症(Glut1DS)就是一个典型的例子。起因于
脑部主要葡萄糖转运蛋白(Glut1)水平低,主要发病于婴儿期或早期
儿童时期,以严重癫痫发作、低脑血糖、认知功能障碍和
复杂的运动障碍,随着年龄的增长而恶化。然而,还没有真正有效的治疗方法来解决
Glut1DS的根本原因,以及对导致Glut1DS的分子和细胞机制知之甚少
这种疾病的表型表现。我们希望解决这些不足之处,并提议这样做
通过开发具有完整人类Glut1基因座的新型人源化Glut1DS模型小鼠-
这项提议的目的。初步工作已经培育出了几个品系的这种小鼠。在.期间
在项目期间,我们将利用成熟的分子电池,对小鼠进行彻底的鉴定,
我们在实验室中优化的细胞和行为分析。该项目将取得成功的结果
这是一个非常有价值的工具,不仅可以探索Glut1DS的基本机制,还可以探索更大的大脑家族的基本机制
能源衰竭综合症。此外,这些小鼠有望在Glut1DS治疗开发中发挥作用;
提高Glut1水平是一种直观上有吸引力的治疗策略和有潜力这样做的药物
最好是在被赋予人类Glut1基因的体内模型中进行测试。
英文摘要
Project Summary
Relative to its size, the human brain consumes a disproportionately large quantity of the body’s total energy
needs. This energy, delivered mainly in the form of glucose, must be readily available and supplied to the
brain on-demand. Failure to do so has dire consequences for the organism, resulting in a state of
neuroglycopenia and, in severe instances, coma and death. While the overt consequence of chronic
neuroglycopenia – cognitive dysfunction – is easily recognized and well-established, its cellular and molecular
correlates are yet to be fully defined. One way of gaining an understanding of the mechanistic details
underlying brain energy deprivation is through the study of genetically determined brain energy failure
syndromes. Glucose Transporter-1 deficiency syndrome (Glut1 DS) is the quintessential example. Caused by
low levels of the principal glucose transporter (Glut1) of the brain, the disease strikes mainly in infancy or early
childhood and is characterized by severe epileptic seizures, low brain glucose, cognitive dysfunction and a
complex movement disorder that worsens with age. Yet, there is no truly effective treatment that addresses
the root cause of Glut1 DS, and little understanding of the molecular and cellular mechanisms that account for
the phenotypic presentation of the disease. We wish to address these deficiencies, and propose to do so
through the development of novel “humanized” Glut1 DS model mice harboring the entire human Glut1 locus –
the objective of this proposal. Preliminary work has already resulted in several lines of these mice. During the
project period, we will thoroughly characterize the mice, employing a battery of well-established molecular,
cellular and behavioral assays that we have optimized in the lab. A successful outcome to the project will result
in an invaluable tool to probe basic mechanisms underlying not just Glut1 DS but also the larger family of brain
energy failure syndromes. Moreover, the mice are expected to prove useful in Glut1 DS therapy development;
raising Glut1 levels is an intuitively appealing therapeutic strategy and agents that have the potential to do so
are best tested in an in vivo model endowed with the human Glut1 gene.
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会议论文
Mechanisms and SMN-independent therapies for spinal muscular atrophy
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批准号:10435837
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资助金额:$57.66万
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财政年份:2022
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负责人:Umrao Monani
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依托单位:
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批准号:10579298
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批准号:10063922
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资助金额:$39.66万
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Spinal muscular atrophy: Mechanisms & treatment strategies.
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批准号:10308474
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资助金额:$39.66万
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财政年份:2018
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依托单位:
The Spinal Muscular Atrophy NMJ phenotype: mechanisms and molecular mediators
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批准号:9385016
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资助金额:$20.0万
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财政年份:2017
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依托单位:
The contributing effects of muscle, nerve and the NMJ to SMA pathology
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批准号:7525404
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资助金额:$33.15万
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财政年份:2008
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依托单位:
The contributing effects of muscle, nerve and the NMJ to SMA pathology
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批准号:7802912
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资助金额:$34.1万
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依托单位:
Novel genetic determinants of the neuromuscular SMA phenotype
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批准号:8660097
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项目类别:
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资助金额:$34.65万
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财政年份:2008
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负责人:Umrao Monani
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依托单位:
The contributing effects of muscle, nerve and the NMJ to SMA pathology
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批准号:8051726
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项目类别:
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资助金额:$33.73万
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财政年份:2008
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负责人:Umrao Monani
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依托单位:
Novel genetic determinants of the neuromuscular SMA phenotype
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批准号:8370078
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项目类别:
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资助金额:$35.0万
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财政年份:2008
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负责人:Umrao Monani
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依托单位:
Novel genetic determinants of the neuromuscular SMA phenotype
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批准号:8468220
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项目类别:
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资助金额:$33.78万
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财政年份:2008
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负责人:Umrao Monani
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依托单位:
The contributing effects of muscle, nerve and the NMJ to SMA pathology
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批准号:7621018
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项目类别:
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资助金额:$34.46万
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财政年份:2008
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负责人:Umrao Monani
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依托单位:
The contributing effects of muscle, nerve and the NMJ to SMA pathology
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批准号:7872728
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项目类别:
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资助金额:$2.43万
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财政年份:2008
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负责人:Umrao Monani
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依托单位:
海外基金