Understanding the cellular basis of Movement Disorders
Understanding the cellular basis of Movement Disorders
批准号:
8631893
负责人:
Puneet Opal
金额:
$37.88万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-08-15 至 2018-06-30
关键词:
Abnormal coordinationAddressAdultAdverse effectsAffectAlzheimer&aposs DiseaseAngiogenic FactorAtaxiaBehavioralBehavioral AssayBiologyBirthBrainBrain StemCAG repeatCategoriesCellsCerebellar AtaxiaCerebellumClinical Trials DesignCytoplasmic GranulesDiseaseEndothelial CellsEventFunctional disorderGene ExpressionGenesGeneticGlutamineGoalsHealthHippocampus (Brain)HumanInferiorInheritedIntraventricularKnock-in MouseKnockout MiceLightMagnetic Resonance ImagingMediatingModelingMotorMovement DisordersMusNatureNerve DegenerationNervous system structureNeurodegenerative DisordersNeurogliaNeuronsOlives - dietaryOnset of illnessOutcome StudyParkinson DiseasePathogenesisPathologyPatientsPeptidesPhenotypePlayPropertyProteinsPurkinje CellsRecombinant Vascular Endothelial Growth FactorRecoveryRoleRouteScheduleSignal TransductionSourceSymptomsSyndromeTechniquesTestingTherapeuticTherapeutic AgentsToxic effectTrinucleotide Repeat ExpansionType 1 Spinocerebellar AtaxiaVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Vascular Endothelial Growth FactorsWorkataxin-1autocrinebasecytokinegene repressionhuman VEGF proteinimprovedinsightmimeticsmouse modelmutantmutant mouse modelnanoparticlenervous system disorderneurotrophic factornovelparacrinepolyglutaminepolyglutamine neurodegenerative diseasespreclinical studypreventpublic health relevanceresearch study
中文摘要
脊髓小脑性共济失调1型(SCA 1)是由脊髓小脑性共济失调引起的九种迟发性神经退行性疾病之一。
多聚谷氨酰胺(CAG)重复序列的扩增。在SCA 1的情况下,致病性谷氨酰胺扩增影响
ataxin-1(ATXN 1),一种在转录抑制中起作用的蛋白质。我们和其他人发现,在SCA 1中,
遗传小鼠模型,突变ATXN 1改变基因表达早在出生后两周,
行为迹象和其他病理事件变得明显。鉴于这些转录的早期性质,
我们预测,一些关键基因的表达改变在发病机制中起着介导作用。在
在测试这一预测的过程中,我们意外地发现ATXN 1直接调节了
血管生成和神经营养细胞因子VEGF的表达,并且其水平在SCA 1中异常低。
老鼠的大脑根据这一观察结果,我们发现基因增加VEGF水平可以减轻
在充分表征的SCA 1敲入小鼠(SCA 1154 Q/2 Q; Q=谷氨酰胺)中的SCA 1表型,
SCA 1小鼠模型。我们还在初步的原理验证实验中证明,
VEGF递送的脑内注射(通过脑室内递送重组VEGF)改善了小脑
SCA 1表型的各个方面,特别是标志性共济失调和小脑树突病理学。动机
通过这些有希望的结果,我们希望检验两个相关的假设:VEGF是一种重要的细胞因子,
在SCA 1的背景下维持神经血管健康,并且VEGF有可能作为治疗SCA 1的方法。
这种无法治愈的疾病我们希望这些研究将提供机械的见解,
SCA 1的发病机制,也有助于设计这种疾病的临床试验。一个重要的辅助结果,
这些研究将阐明VEGF在神经系统中的基础生物学,
在其他神经退行性综合征中的作用。
英文摘要
Spinocerebellar ataxia type 1 (SCA1) is one of nine late-onset neurodegenerative diseases caused by the
expansion of a polyglutamine (CAG) repeat. In the case of SCA1, the pathogenic glutamine expansion affects
ataxin-1 (ATXN1), a protein that plays a role in transcriptional repression. We and others have found that in SCA1
genetic mouse models, mutant ATXN1 alters gene expression as early as two weeks after birth, long before
behavioral signs and other pathological events become evident. Given the early nature of these transcriptional
aberrations, we predicted that altered expression of a few key genes plays a mediatory role in pathogenesis. In
the course of testing this prediction, we made the unexpected discovery that ATXN1 directly regulates the
expression of the angiogenic and neurotrophic cytokine VEGF and that its levels are abnormally low in the SCA1
mouse brain. Following up on this observation, we discovered that genetically increasing VEGF levels mitigates
the SCA1 phenotype in the well-characterized SCA1 knock-in mouse (SCA1154Q/2Q; Q=glutamine), the best
existing mouse model of SCA1. We have also demonstrated in preliminary proof-of-principle experiments that
VEGF delivered pharmacologically (by intraventricular delivery of recombinant VEGF) improves the cerebellar
aspects of the SCA1 phenotype, specifically the hallmark ataxia and the cerebellar dendritic pathology. Motivated
by these promising results, we wish to test two related hypotheses: that VEGF is an important cytokine for
maintaining neurovascular health in the context of SCA1, and that VEGF has the potential to serve as therapy for
this otherwise untreatable disease. We hope that these studies will provide mechanistic insights into the
pathogenesis of SCA1 and also help design clinical trials for this disease. An important ancillary outcome of
these studies is that they would shed light on the basic biology of VEGF in the nervous system and provide clues
to its role in other neurodegenerative syndromes.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
VEGF-Mimetic Supramolecular Nanoparticles for Treating Spinocerebellar Ataxia Type 1
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批准号:8876831
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资助金额:$37.88万
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Understanding the Cellular Basis of Movement Disorders
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Understanding the Cellular Basis of Movement Disorders
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批准号:10403448
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Understanding the cellular basis of Movement Disorders
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依托单位:
Cellular pathways underlying polyglutamine degeneration
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批准号:8251361
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依托单位:
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Cellular pathways underlying polyglutamine degeneration
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Cellular pathways underlying polyglutamine degeneration
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Cellular pathways underlying polyglutamine degeneration
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Role of Leucine-rich Acidic Proteins in Neuronal Development
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资助金额:$32.69万
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财政年份:2010
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依托单位:
Cellular pathways underlying polyglutamine degeneration
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财政年份:2008
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负责人:Puneet Opal
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依托单位:
Molecular Basis of Spinocerebellar Ataxia Type 1
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依托单位:
海外基金