Development of Visual Connections

视觉联系的发展

基本信息

批准号：
9915921
负责人：
Carla J Shatz
金额：
$ 41.28万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-01-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915921
关键词：
APP-PS1 Adolescent Adult Affinity Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Amaze Amblyopia Amino Acids Amyloid beta-Protein Anatomy Animal Model Appearance Binding Blindness Brain Cells Cerebral cortex Child Clinical Dendritic Spines Development Disease Electroporation Engineering Epitopes Expression Profiling Functional disorder Genotype Goals Growth Hippocampus (Brain)Histocompatibility Human Image Immune Immunoglobulins Knock-out Knockout Mice Knowledge Laboratories Learning Life Ligand Binding Ligands Measures Memory Memory Loss Methods Molecular Mus Natural regeneration Neurodegenerative Disorders Neurons Ocular Dominance Outcomes Research Pathogenicity Peptides Photons Physiological Process Prosencephalon Protein Engineering Proteins Reagent Recombinant Proteins Recombinants Recovery Regulation Research Research Proposals RiboTag Ribosomal Proteins Role Savings Signal Pathway Signal Transduction Structure Sum Synapses Synaptic plasticity Techniques Testing Training Transcript Transgenic Mice Vertebral column Visual Cortex Visual system structure Work Yeasts abeta oligomer brain repair candidate identification cell type clinically relevant cofilin cognitive enhancement congenital cataract critical developmental period critical period density design experience experimental study functional restoration hippocampal pyramidal neuron in utero in vivo imaging mRNA Expression mouse model neural circuit new therapeutic target novel novel therapeutics prevent public health research receptor repaired restoration transcriptome transcriptome sequencing vision development visual deprivation

项目摘要

7. Project Summary What enables a baby's brain to learn so rapidly during early developmental critical periods? Is it possible to re- engage in adult the enhanced learning capacity present in the child's brain for repair or restoration of function? We have discovered that a neuronal receptor called PirB (Paired Immunoglobulin-like receptor B; human LilrB2/3) regulates synapse pruning and plasticity in cerebral cortex. Blocking PirB function in visual cortex rapidly leads to new dendritic spines and functional synapses even in adult. These observations have clinical relevance. A hallmark of Alzheimer's disease (AD) is loss of plasticity and excessive synapse pruning. But when PirB is knocked out in a mouse model of AD, mice are protected from memory loss. Moreover, new synapses generated by PirB blockade can be captured to facilitate recovery from severe vision loss in Amblyopia. A major goal of this research proposal is to save or regenerate synapses by understanding cell and molecular mechanisms of how PirB regulates synapse pruning. Three specific aims are proposed. 1) Assess effects of PirB deletion on dendritic spine density and stability in visual cortex. We have generated mice with a conditional allele of PirB (PirB flox/flox). We have also made a soluble PirB function- blocking recombinant protein: sPirB. These mice and reagents permit cell-type specific and temporal disruption of PirB and will be used in 2 photon imaging and physiological studies of synapse pruning and spine turnover in cortical pyramidal neurons. Results from these experiments should illuminate further how PirB regulates plasticity and synapse pruning in juvenile and adult visual cortex. 2) Investigate how PirB functions by using expression profiling to identify PirB signaling pathways. Preliminary experiments suggest that cofilin signaling contributes to PirB dependent regulation of dendritic spine density, and is hyperactivated in a mouse model of AD. Here an unbiased approach to identify PirB-driven alterations in mRNA expression is proposed. RiboTag mice will be used to isolate neuronal transcripts from PirB+/+ vs PirB-/- visual cortex. Using microarrays and RNAseq, the transcriptomes of the 2 genotypes will be analyzed and compared. This approach should facilitate identification of candidate signaling pathways regulated by PirB. 3) PirB and Alzheimer's disease- Engineer high affinity, specific blockers of the PirB-Abeta interaction. We have measured a direct interaction between PirB and soluble oligomers of beta amyloid (Abeta), the pathogenic 42 amino acid peptide in AD. The PirB-Abeta interaction represents a novel and potentially pivotal signaling axis. Protein engineering techniques including yeast display and affinity maturation will be used to create molecular entities able to block the Abeta-PirB (or Abeta-LilrB2 in human) interaction, potentially yielding new drug targets to treat AD. In sum, this proposal seeks to extend understanding of PirB function and dysfunction towards the ultimate goal of designing novel therapies that can regenerate lost synapses, thereby restoring function to neural circuits whose connections have been altered by abnormal experience or disease.

7。项目摘要是什么使婴儿的大脑能够在早期发育的关键时期迅速学习？是否可以重新参与成年人的大脑中存在的增强学习能力以修复或恢复功能？我们发现一种称为PIRB的神经元受体（成对的免疫球蛋白样受体B;人 LILRB2/3）调节脑皮质中的突触修剪和可塑性。在视觉皮层中阻止PIRB功能即使在成年人中，也会迅速导致新的树突状刺和功能突触。这些观察结果有临床关联。阿尔茨海默氏病（AD）的标志是损失可塑性和过度的突触修剪。但当PIRB在AD的小鼠模型中拆除时，将保护小鼠免受记忆损失。而且，新的可以捕获由PIRB封锁产生的突触，以促进从严重视力丧失中恢复弱视。该研究建议的主要目标是通过了解细胞和 PIRB如何调节突触修剪的分子机制。提出了三个具体目标。 1）评估 PIRB缺失对视觉皮层的树突状脊柱密度和稳定性的影响。我们已经产生了用 PIRB（PIRB Flox/Flox）的条件等位基因。我们还制作了可溶的PIRB函数 - 阻止重组蛋白质：螺旋。这些小鼠和试剂允许细胞类型的特异性和时间破坏PIRB，将是用于2个光子成像和突触修剪和脊柱周转的生理研究神经元。这些实验的结果应进一步阐明PIRB如何调节可塑性和突触在少年和成人视觉皮层中修剪。 2）研究PIRB如何通过使用表达分析到识别PIRB信号通路。初步实验表明Cofilin信号传导有助于PIRB 树突状脊柱密度的依赖性调节，并在AD的小鼠模型中过度激活。在这里提出了公正的方法来鉴定PIRB驱动的mRNA表达改变。 Ribotag小鼠将是用于将神经元转录本与PIRB+/+与PIRB - / - 视觉皮层分离。使用微阵列和RNASEQ，将分析和比较两种基因型的转录组。这种方法应促进识别由PIRB调节的候选信号通路。 3）PIRB和阿尔茨海默氏病 - 工程师高亲和力， PIRB-ABETA相互作用的特定阻滞剂。我们测量了PIRB和 β-淀粉样蛋白（ABETA）的可溶性低聚物，AD中的致病性42氨基酸肽。 pirb-abeta 相互作用代表了一种新颖且潜在的关键信号轴。蛋白质工程技术包括酵母展示和亲和力成熟将用于创建能够阻止Abeta-Pirb的分子实体（或人类相互作用中的Abeta-lilrb2，有可能产生新的药物来治疗AD。总而言之试图将对PIRB功能和功能障碍的理解扩展到设计小说的最终目标可以再生突触损失的疗法，从而将功能恢复为神经回路的功能异常经验或疾病改变了。