Building Synaptic Cytoskeleton

构建突触细胞骨架

• 批准号: 10621766
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621766
• 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; Dissociation; 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; Molecular; Mutation; Nature; Nerve Degeneration; Neurons; Phase; Polymers; Process; Proteins; Regulation; Role; Schizophrenia; Shapes; Stimulus; Structure; Synapses; Testing; Thinness; Time; Vertebral column; autism spectrum disorder; data acquisition; experimental study; falls; flexibility; genetic approach; genetic regulatory protein; interest; monomer; mutant; nano; pharmacologic; polymerization; postsynaptic; response; scaffold; superresolution microscopy; synaptogenesis; trafficking; 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; Dissociation; 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; Molecular; Mutation; Nature; Nerve Degeneration; Neurons; Phase; Polymers; Process; Proteins; Regulation; Role; Schizophrenia; Shapes; Stimulus; Structure; Synapses; Testing; Thinness; Time; Vertebral column; autism spectrum disorder; data acquisition; experimental study; falls; flexibility; genetic approach; genetic regulatory protein; interest; monomer; mutant; nano; pharmacologic; polymerization; postsynaptic; response; scaffold; superresolution microscopy; 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锚突触粘附分子，并生成灵活的结构 树突状脊柱形状表征。它调节和支持膜流量并定义突触 车厢。它还驱动了新的突触的产生以及突触大小和形状的持久变化 这是响应显着刺激而发生的。这些是长期存在的，广泛接受的事实。宽阔 接受这些事实使人们更加令人惊讶的是，对突触肌动蛋白的了解很少 生成。当新的突触形成时，是什么驱动其组装的原因，此过程与此过程有何不同 驱动脊柱膨胀或收缩的重组？知识的差距限制了对 阿尔茨海默氏病和相关痴呆症，突触丧失和脊柱形状变化很好 记录。它还影响脑部疾病和病理，包括肌萎缩性侧索硬化症， 精神分裂症，智力残疾和自闭症，可以在肌动蛋白的突变，损失或增益中播种 调节功能和涉及突触可塑性机制（例如药物）机制的疾病 瘾。知识的差距不是疏忽，也不是由于缺乏兴趣。它存在是因为突触是 小而难以研究，肌动蛋白丝非常薄，脆弱和动态，几个分子 直到最近才发现对核肌动蛋白重要的成分。该提议的目的是 确定与突触产生相关的主要肌动蛋白成核器，并评估时间，地点和 他们行动的上下文。不知道相关的球员是该领域和拟议的速率限制步骤 实验是识别与特定特定的肌动蛋白支架的性质和位置的第一步 突触形成，生物学作用（例如粘附或贩运）或状态变化的阶段（例如 增强或抑郁）。