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