Building Synaptic Cytoskeleton

构建突触细胞骨架

• 批准号: 10241547
• 负责人: Deanna L Benson
• 金额: $ 45.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241547
• 关键词: Actins; Adhesions; Aging; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Architecture; Biological; Brain Diseases; Brain Pathology; Cell Adhesion Molecules; Characteristics; Chemosensitization; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Cytoskeleton; Data; Dementia; Dendritic Spines; Development; Disease; Drug Addiction; Event; Family; Filament; G Actin; Generations; Genes; Goals; Image; Impaired cognition; Intellectual functioning disability; Knock-out; Knowledge; Learning; Location; Membrane Protein Traffic; Memory; Mental Depression; Microfilaments; Microscopy; Molecular; Mutation; Nature; Nerve Degeneration; Neurons; Pharmacology; Phase; Process; Proteins; Regulation; Role; Schizophrenia; Shapes; Stimulus; Structure; Synapses; Testing; Thinness; Time; Vertebral column; autism spectrum disorder; base; data acquisition; experimental study; falls; flexibility; genetic approach; genetic regulatory protein; interest; monomer; mutant; polymerization; postsynaptic; response; scaffold; synaptogenesis; trafficking

The actin cytoskeleton anchors synapse adhesion molecules and generates the flexible architecture that characterizes dendritic spine shape. It regulates and supports membrane traffic and defines synapse compartments. It also drives the generation of new synapses and lasting changes in synapse size and shape that occur in response to salient stimuli. These are long-standing, widely accepted facts. The broad acceptance of these facts makes it all the more surprising that relatively little is known about how synaptic actin is generated. What drives its assembly when new synapses are forming, and how does this process differ from the reorganization that drives spine expansion or shrinkage? This gap in knowledge limits the understanding of Alzheimer's Disease and related dementias where synapse loss and changes in spine shape are well documented. It also impacts brain disorders and pathologies, including amyotrophic lateral sclerosis, schizophrenia, intellectual disability and autism, that can be seeded in the mutation, loss, or gain of actin regulatory function, and disorders that involve derailed mechanisms of synapse plasticity such as drug addiction. This gap in knowledge is not an oversight or due to lack of interest. It exists because synapses are small and difficult to study, actin filaments are exceptionally thin, fragile and dynamic, and several molecular components important for nucleating actin have only recently been identified. The purpose of this proposal is to identify the principal actin nucleators relevant to the generation of synapses, and to assess the time, place, and context in which they act. Not knowing the relevant players is a rate limiting step in the field and the proposed experiments are a first step toward identifying the nature and location of actin scaffolds relevant to particular stages of synapse formation, biological actions (e.g. adhesion or trafficking) or to changes in state (e.g. potentiation or depression).

肌动蛋白细胞骨架锚定突触黏附分子，并产生灵活的结构， 具有树枝状脊椎形状的特征。它调节和支持膜交通，并定义突触 车厢。它还驱动新突触的产生和突触大小和形状的持久变化 发生在对显著刺激的反应中。这些都是由来已久、广为接受的事实。《博大》 对这些事实的接受使人们更加惊讶地发现，人们对突触肌动蛋白是如何 是生成的。当新的突触形成时，是什么驱动它的组装，这个过程与 推动脊柱扩张或收缩的重组？这种知识上的差距限制了人们对 突触丢失和脊柱形状变化良好的阿尔茨海默病和相关痴呆 有记录在案。它还影响大脑紊乱和病理，包括肌萎缩侧索硬化症， 精神分裂症、智力残疾和自闭症，这些都可能是肌动蛋白突变、丢失或获得的种子 调节功能，以及涉及突触可塑性机制脱轨的障碍，如药物 上瘾。这种知识上的差距不是疏忽，也不是因为缺乏兴趣。它的存在是因为突触 肌动蛋白细丝很小，很难研究，它特别薄，很脆弱，很有活力，有几个分子 肌动蛋白核化的重要成分直到最近才被发现。这项建议的目的是 确定与突触生成相关的主要肌动蛋白核因子，并评估时间、地点和 他们采取行动的背景。不知道相关玩家是该领域的速率限制步骤，建议的 实验是确定肌动蛋白支架的性质和位置的第一步 突触形成的阶段、生物行为(如黏附或运输)或状态的变化(如： 增强或抑制)。