Novel AAV Capsids and Gene Regulatory Elements for GeneExpression in Microglia
用于小胶质细胞基因表达的新型 AAV 衣壳和基因调控元件
基本信息
- 批准号:10195876
- 负责人:
- 金额:$ 24万
- 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:2021-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAlzheimer&aposs disease therapyAutomobile DrivingBindingBlood - brain barrier anatomyBrainBrain DiseasesCapsidCell NucleusCell surfaceCellsChromatinCodeCommunitiesDNADataDegradation PathwayDependovirusDevelopmentDiseaseElementsEngineeringEnzymesExhibitsGene ExpressionGenesGenetic studyGenomeGoalsImmunohistochemistryIn Situ HybridizationIn VitroIndividualInjectionsLabelLate Onset Alzheimer DiseaseLentivirusLibrariesLinkMediatingMicrogliaMusNeurosciencesNeurosciences ResearchOutcomePlayPublishingRNARare DiseasesRegulator GenesRegulatory ElementResistanceRoleSafetySchizophreniaSliceSynapsesTestingTimeTransgenic AnimalsTransgenic MiceVariantViralViral GenomeViral VectorVirusWorkadeno-associated viral vectorblood-brain barrier crossingbrain cellcell typecomplement systemgene therapyhuman embryonic stem cellimprovedin vivoin vivo evaluationinhibitor/antagonistmacrophagenovelparticlepreventprotein degradationrisk varianttooltraffickingtransgene expressionvector genome
项目摘要
Project Summary:
Microglia, the resident macrophages of the brain, assume a multitude of functions during brain development and
disease. Long known to react to changes in brains affected by Alzheimer’s disease (AD), genetic studies of late-
onset AD indicate that AD risk variants are commonly found in or near genes that are specifically expressed in
microglia, suggesting that microglia play an active role in driving AD. In addition, microglia exhibit various
functions during brain development, including synapse pruning. Genes coding for components of the
complement system, which mediates synapse pruning by microglia, have been linked to schizophrenia.
However, a major bottleneck in studying the roles of microglia in normal and diseased brains is the lack of viral
tools for rapidly manipulating their gene expression. Viral vectors would also benefit studies where transgenic
animals are not available. Finally, viral vectors would enable studies on the potential of gene therapy for AD and
rare diseases that affect microglia. However, while microglia show modest and localized transduction by
lentiviruses in vivo, they are resistant to transduction by adeno-associated viruses (AAVs), the preferred viral
vectors used in neuroscience research and gene therapy due to their superior spread and excellent safety profile.
Here we propose to elucidate the barriers to microglia transduction by AAVs, engineer AAV capsid variants that
are able to overcome these barriers and transduce microglia in vivo, and develop novel gene regulatory elements
that will enable microglia-specific transgene expression from viral vectors. This will be a collaborative project
between the Stevens and Deverman labs, combining their expertise in studying microglia (Stevens) and in
developing novel AAV vectors (Deverman).
项目概要:
小胶质细胞是大脑的常驻巨噬细胞,在大脑发育期间承担多种功能,
疾病长期以来,人们都知道阿尔茨海默病(AD)会对大脑的变化做出反应,最近的遗传研究表明,
AD发作表明AD风险变异体通常存在于或接近于在AD中特异性表达基因中,
小胶质细胞,表明小胶质细胞在驱动AD中发挥积极作用。此外,小胶质细胞表现出各种
大脑发育过程中的功能,包括突触修剪。基因编码的组成部分,
通过小胶质细胞介导突触修剪的补体系统与精神分裂症有关。
然而,研究小胶质细胞在正常和患病大脑中的作用的一个主要瓶颈是缺乏病毒表达。
快速操纵基因表达的工具。病毒载体也将有利于转基因的研究,
没有动物可用。最后,病毒载体将使研究基因治疗AD的潜力成为可能,
影响小胶质细胞的罕见疾病。然而,虽然小胶质细胞显示出适度的和局部的转导,
在体内,它们对腺相关病毒(AAV)的转导具有抗性,优选的腺相关病毒(AAV)是慢病毒。
由于它们的上级扩散性和极好的安全性,它们被用于神经科学研究和基因治疗。
在这里,我们建议阐明AAV对小胶质细胞转导的障碍,工程化AAV衣壳变体,
能够克服这些障碍,在体内抑制小胶质细胞,并开发新的基因调控元件,
这将使小胶质细胞特异性转基因能够从病毒载体表达。这将是一个合作项目
史蒂文斯和德弗曼实验室之间,结合他们在研究小胶质细胞(史蒂文斯)和
开发新的AAV载体(Deverman)。
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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Benjamin E Deverman其他文献
Benjamin E Deverman的其他文献
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{{ truncateString('Benjamin E Deverman', 18)}}的其他基金
Novel AAV Capsids and Gene Regulatory Elements for GeneExpression in Microglia
用于小胶质细胞基因表达的新型 AAV 衣壳和基因调控元件
- 批准号:
10376863 - 财政年份:2021
- 资助金额:
$ 24万 - 项目类别:
Development and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species.
开发和验证 AAV 载体,以操纵哺乳动物物种中与癫痫和精神疾病有关的特定神经元亚型和回路。
- 批准号:
9804329 - 财政年份:2019
- 资助金额:
$ 24万 - 项目类别:
Development and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species.
开发和验证 AAV 载体,以操纵哺乳动物物种中与癫痫和精神疾病有关的特定神经元亚型和回路。
- 批准号:
10001022 - 财政年份:2019
- 资助金额:
$ 24万 - 项目类别:
Development and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species.
开发和验证 AAV 载体,以操纵哺乳动物物种中与癫痫和精神疾病有关的特定神经元亚型和回路。
- 批准号:
10170428 - 财政年份:2019
- 资助金额:
$ 24万 - 项目类别:
Development and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species.
开发和验证 AAV 载体,以操纵哺乳动物物种中与癫痫和精神疾病有关的特定神经元亚型和回路。
- 批准号:
10612519 - 财政年份:2019
- 资助金额:
$ 24万 - 项目类别:
Novel AAVs engineered for efficient and noninvasive cross-species gene editing throughout the central nervous system
新型 AAV 专为整个中枢神经系统进行高效、非侵入性的跨物种基因编辑而设计
- 批准号:
10455344 - 财政年份:2018
- 资助金额:
$ 24万 - 项目类别:
Novel AAVs engineered for efficient and noninvasive cross-species gene editing throughout the central nervous system
新型 AAV 专为整个中枢神经系统进行高效、非侵入性的跨物种基因编辑而设计
- 批准号:
10001044 - 财政年份:2018
- 资助金额:
$ 24万 - 项目类别:
Novel AAVs engineered for efficient and noninvasive cross-species gene editing throughout the central nervous system
新型 AAV 专为整个中枢神经系统进行高效、非侵入性的跨物种基因编辑而设计
- 批准号:
9789390 - 财政年份:2018
- 资助金额:
$ 24万 - 项目类别:
Novel AAVs Engineered for Efficient and Noninvasive Cross-Species Gene Editing Throughout the Central Nervous System
专为整个中枢神经系统进行高效、非侵入性跨物种基因编辑而设计的新型 AAV
- 批准号:
10490394 - 财政年份:2018
- 资助金额:
$ 24万 - 项目类别:
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