Enhancement, mapping, and validation of viral vectors for primate optogenetics
用于灵长类光遗传学的病毒载体的增强、绘图和验证
基本信息
- 批准号:10391957
- 负责人:
- 金额:$ 68.87万
- 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 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AnatomyAnimal ModelAnimalsAreaAtlasesBasic ScienceBehaviorBrainBrain DiseasesCapsidCellsChronicComplexDependovirusDiseaseElectrophysiology (science)EnzymesFDA approvedGene ExpressionGenesGeneticGlycoproteinsGoalsHistologicHumanImmune responseImmune systemImmunologyInjectionsInnate Immune ResponseInterventionLentivirusLentivirus VectorLightMacacaMapsMediatingMethodsModelingModernizationMolecularMonkeysNeurobiologyNeuronsNeurosciencesOpsinOutcomeOutputPatternPharmaceutical PreparationsPharmacologyPhysiologicalPopulation ProjectionPrimatesProteinsProtocols documentationRegimenResearchRodentRoleSirolimusSiteSpecificitySystemT-LymphocyteTechniquesTechnologyTopoisomeraseTopoisomerase InhibitorsTransduction GeneTransgenesTransportationV1 neuronValidationViralViral VectorVirusVisionVision researchVisualVisual system structureWorkadaptive immune responsearmbasebrain disorder therapycell typeeffective therapyefficacy evaluationefficacy validationfrontal eye fieldsgene therapyimprovedin vivoin vivo evaluationinhibitorinsightinterestneural circuitneuronal circuitryneurophysiologynonhuman primatenovel therapeuticsoculomotoroptogeneticsorbit musclepreventpromoterreagent testingrecruitrelating to nervous systemretrograde transportsuccesssuperior colliculus Corpora quadrigeminatherapeutic genetooltransgene deliverytransgene expressionvectorvirologyvisual controlvisual motorvisual neuroscience
项目摘要
PROJECT SUMMARY
Mapping the visual and visuomotor circuits of the brain using opsins and other actuators to target and control
neurons is a central goal of modern neuroscience. Actuators have become key to studying neuronal circuits,
modeling brain disorders, and developing new therapies. Neural actuator applications to research in rodents and
other small animals have achieved great success. In primates, however, these approaches have yet to be
transformative. The main problem is that viral vectors are required to deliver actuator genes, but both viral
transduction and gene expression have been unreliable across, and even within, primate labs. Efficacy is
hindered by the complex innate and adaptive retaliatory immune response in primates, and even when the
approach does work, cell-type specificity is lacking. The overall purpose of this project is to incorporate recent
advances in virology, gene therapy, and immunology to maximize viral transduction, maintain chronic gene
expression, and gain cell-type specificity through retrograde transportation of viruses in visual circuits of the
macaque brain. Throughout the project, optogenetics is the actuator-mediated intervention and the visual-
oculomotor system is the testbed. We focus on two viruses that provide retrograde transport: retrograde adeno-
associated virus-2 (rAAV2-retro) and fusion glycoprotein-E pseudotyped lentiviral vector (NeuRet). Each will
deliver genes encoding the Red-activatable Channelrhodopsin (ReaChR). Our team, spanning Duke, NYU, and
UNC-Chapel Hill, has extensive expertise in vector technology and macaque neurobiology. Aim 1 is dedicated
towards the maturation of pharmacological regimens that modify both arms of the primate's immune system to
enhance viral transduction and promote long-term constitutive expression of opsin transgenes. Aim 2 will
establish comprehensive expression maps of retrogradely transduced neurons. This mapping is a critical step
toward providing cell- and circuit-level specificity and supplies a means for physiologically identifying neurons,
through phototagging, based on their anatomical connectivity. Aim 3 will use phototagging paired with projection
targeting to identify and neurophysiologically characterize neurons contributing to specific circuits within the
visual and visuomotor circuitry of the macaque brain. In combination, this work will enhance the efficacy of viral
vectors for neuroscientific research of the macaque visual and visuomotor system, provide both anatomical and
functional validation of the developed protocols, and provide new insights into the functional role these specific
circuits serve in vision and visuomotor behaviors. Finally, this project will provide fundamental insights for
improving human gene therapies that depend on viral delivery of therapeutic genes.
项目摘要
使用视蛋白和其他致动器来定位和控制大脑的视觉和视觉回路
神经元是现代神经科学的核心目标。致动器已经成为研究神经元回路的关键,
模拟脑部疾病,开发新的疗法神经致动器在啮齿动物研究中的应用
其他小动物也取得了巨大的成功。然而,在灵长类动物中,这些方法还没有被应用。
变革主要的问题是,病毒载体需要提供致动基因,但无论是病毒载体,
在灵长类动物实验室中,甚至在灵长类动物实验室内,转导和基因表达都是不可靠的。疗效
受到灵长类动物复杂的先天性和适应性报复性免疫反应的阻碍,甚至当
方法确实有效,但缺乏细胞类型特异性。该项目的总体目的是将最近的
病毒学、基因治疗和免疫学的进展,以最大限度地提高病毒转导,维持慢性基因转移,
表达,并获得细胞类型的特异性,通过逆行运输的病毒在视觉电路的
猕猴脑在整个项目中,光遗传学是致动器介导的干预和视觉-
眼科系统是试验平台。我们专注于两种提供逆行转运的病毒:逆行腺病毒,
相关病毒-2(rAAV 2-retro)和融合糖蛋白-E假型慢病毒载体(NeuRet)。双方都将
递送编码红色可激活的视紫红质(ReaChR)的基因。我们的团队,跨越杜克,纽约大学,
北卡罗来纳大学教堂山分校在载体技术和猕猴神经生物学方面拥有广泛的专业知识。Aim 1致力于
朝着药物治疗方案的成熟发展,这些药物治疗方案可以改变灵长类动物免疫系统的双臂,
增强病毒转导和促进视蛋白转基因的长期组成型表达。目标2将
建立逆行转导神经元的综合表达图谱。这种映射是关键的一步
旨在提供细胞和电路水平的特异性,并提供了一种用于生理学识别神经元的方法,
通过照片标记,基于它们的解剖连接。AIM 3将使用与投影配对的照片标记
靶向以识别和神经生理学表征对脑内特定回路有贡献的神经元。
猕猴大脑中的视觉和视觉回路。结合起来,这项工作将提高病毒的功效。
猕猴视觉和视觉系统神经科学研究的载体,提供解剖学和
功能验证的开发协议,并提供新的见解的功能作用,这些具体的
电路在视觉和视觉行为中起作用。最后,该项目将提供基本的见解,
改进依赖于治疗基因的病毒递送的人类基因疗法。
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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Marc A Sommer其他文献
The feeling of looking
看的感觉
- DOI:
10.1038/nn0507-538 - 发表时间:
2007-05-01 - 期刊:
- 影响因子:20.000
- 作者:
Marc A Sommer - 通讯作者:
Marc A Sommer
Marc A Sommer的其他文献
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{{ truncateString('Marc A Sommer', 18)}}的其他基金
Enhancement, mapping, and validation of viral vectors for primate optogenetics
用于灵长类光遗传学的病毒载体的增强、绘图和验证
- 批准号:
10546445 - 财政年份:2022
- 资助金额:
$ 68.87万 - 项目类别:
Neuromuscular Control of Primate Eye Movements
灵长类动物眼球运动的神经肌肉控制
- 批准号:
9919573 - 财政年份:2019
- 资助金额:
$ 68.87万 - 项目类别:
2017 Eye Movements Gordon Research Conference and Gordon Research Seminar
2017眼动戈登研究会议暨戈登研究研讨会
- 批准号:
9331202 - 财政年份:2017
- 资助金额:
$ 68.87万 - 项目类别:
Impact of Timing, Targeting, and Brain State on rTMS of Human and Non-Human Primates
时间、目标和大脑状态对人类和非人类灵长类动物 rTMS 的影响
- 批准号:
9390539 - 财政年份:2017
- 资助金额:
$ 68.87万 - 项目类别:
Effects of Transcranial Magnetic Stimulation on Neurons in Behaving Primates
经颅磁刺激对行为灵长类动物神经元的影响
- 批准号:
8285060 - 财政年份:2012
- 资助金额:
$ 68.87万 - 项目类别:
Functions of Saccadic Circuits in Lateral Cerebellar Cortex
小脑外侧皮层扫视回路的功能
- 批准号:
8523897 - 财政年份:2012
- 资助金额:
$ 68.87万 - 项目类别:
Effects of Transcranial Magnetic Stimulation on Neurons in Behaving Primates
经颅磁刺激对行为灵长类动物神经元的影响
- 批准号:
8412767 - 财政年份:2012
- 资助金额:
$ 68.87万 - 项目类别:
Functions of Saccadic Circuits in Lateral Cerebellar Cortex
小脑外侧皮层扫视回路的功能
- 批准号:
8359944 - 财政年份:2012
- 资助金额:
$ 68.87万 - 项目类别:
Visuomotor functions of ascending pathways to frontal cortex
额叶皮层上升通路的视觉运动功能
- 批准号:
7908752 - 财政年份:2006
- 资助金额:
$ 68.87万 - 项目类别:
Visuomotor functions of ascending pathways to frontal cortex
额叶皮层上升通路的视觉运动功能
- 批准号:
7130992 - 财政年份:2006
- 资助金额:
$ 68.87万 - 项目类别:
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