Building Synaptic Cytoskeleton

构建突触细胞骨架

• 批准号: 10413252
• 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/10413252
• 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粘附分子并产生灵活的结构 表征树突棘的形状。它调节和支持膜交通并定义突触 隔间。它还推动新突触的产生以及突触大小和形状的持久变化 是对显着刺激的反应而发生的。这些都是长期存在的、被广泛接受的事实。广义的 接受这些事实后，人们对突触肌动蛋白如何发挥作用知之甚少，这让人更加感到惊讶。 被生成。当新突触形成时，是什么驱动其组装，这个过程与传统突触有何不同？ 导致脊柱扩张或收缩的重组？这种知识上的差距限制了人们的理解 阿尔茨海默氏病和相关痴呆症，其中突触损失和脊柱形状的变化很好 记录在案。它还会影响大脑疾病和病理，包括肌萎缩侧索硬化症、 精神分裂症、智力障碍和自闭症，这些都可能因肌动蛋白的突变、缺失或增加而产生 调节功能，以及涉及突触可塑性脱轨机制的疾病，例如药物 瘾。这种知识差距并非疏忽或缺乏兴趣所致。它的存在是因为突触 肌动蛋白丝很小且难以研究，但它非常细、脆弱且动态，并且有几个分子 对于成核肌动蛋白重要的成分最近才被鉴定出来。该提案的目的是 识别与突触生成相关的主要肌动蛋白成核剂，并评估时间、地点和 他们行动的背景。不了解相关参与者是该领域的一个速率限制步骤，建议 实验是确定与特定肌动蛋白支架相关的性质和位置的第一步 突触形成的阶段、生物作用（例如粘附或运输）或状态变化（例如 增强或抑制）。