Integrin Signaling Through Arg Kinase Regulates Synapse, Dendrite Stabilization

通过精氨酸激酶的整合素信号调节突触和树突稳定

• 批准号: 8197976
• 负责人: Michael Sloan Warren
• 金额: $ 2.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197976
• 关键词: Address; Adhesions; Adult; Age; Age-associated memory impairment; Alzheimer' s Disease; Animals; Apoptosis; Atrophic; Behavioral; Binding; Biochemical; Brain; Cells; Cerebral cortex; Cytoskeleton; Data; Dendrites; Dendritic Spines; Development; Disease; Dose; Dyes; ECM receptor; Economic Burden; Electron Microscopy; Ensure; Excitatory Synapse; Exhibits; Failure; Fibroblasts; Genes; Genetic; Goals; Hippocampus (Brain); Housing; Human; Impaired cognition; Integrins; Lead; Life; Maintenance; Measures; Mediating; Mus; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurons; Pathology; Pathway interactions; Patients; Phosphotransferases; Prefrontal Cortex; Preparation; Process; Protein Tyrosine Kinase; Relative (related person); Research; Research Training; Risk Factors; Severities; Signal Transduction; Synapses; Tail; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Time Study; in vivo; neuron loss; neurotransmission; new therapeutic target; novel; novel therapeutic intervention; object recognition; postnatal; prevent; public health relevance; receptor; research study; social

DESCRIPTION (provided by applicant): Integrin signaling through Arg kinase regulates synapse and dendrite stabilization. Synapses in the human brain must be actively maintained over extended periods of time to ensure the efficacy of neuronal transmission and overall brain function. The failure to properly maintain synapses is thought to contribute to age-related cognitive decline and the pathology of numerous neurodegenerative disorders such as Alzheimer's disease. Understanding the mechanisms of synaptic maintenance may lead to new therapeutic approaches to reduce synapse loss and may identify risk factors for age- and disease-related neurodegeneration. Recent research has identified a pathway involving the Arg tyrosine kinase that is essential for synapse and dendrite maintenance. The overall aim of this project is to identify what upstream signals regulate Arg activity at the synapse and determine what effects those signals have on synapse and dendrite stability. Previous studies in non-neuronal cells have demonstrated that integrins, which are receptors for extracellular matrix components, signal through Arg to coordinate adhesion and cytoskeletal dynamics. This project will test the hypothesis that an integrin/Arg interaction promotes synapse stability in vivo. Hippocampal synapses will be quantified in crosses between arg and integrin¿1 mutant mice at different ages via electron microscopy. As Arg activity also regulates dendritic stability, dendritic arbors will be reconstructed in mutant mice by dye-filling live hippocampal neurons. The experiments outlined in this proposal will also determine if integrins signal through Arg kinase by biochemically measuring the relative activity of known Arg substrates in integrin¿1 mutant mice. Finally, this project aims to determine the behavioral relevance of the putative integrin/Arg interaction by measuring overall hippocampal function in mutant mice through a novel object recognition task. Through complementary use of genetic, biochemical, and behavioral techniques, this project seeks to identify and characterize an integrin-dependent signaling cascade that promotes synapse and dendrite maintenance. The long-term goal of this line of research is to fully understand what mechanisms stabilize synapses in vivo. PUBLIC HEALTH RELEVANCE: Integrin signaling through Arg kinase regulates synapse and dendrite stabilization Age- and disease-related neurodegeneration extracts an immense personal, social, and economic burden worldwide. As the loss of synapses, which are the connections between neurons, is a common pathology in many forms of neurodegeneration, therapeutic interventions that artificially stabilize synapses may have wide- ranging applications. This project will characterize a novel biochemical mechanism that promotes synapse stability in an effort to identify new therapeutic targets.

描述（由申请人提供）：整合素信号通过Arg激酶调节突触和树突稳定。人脑中的突触必须在长时间内得到积极维护，以确保神经元传递的有效性和大脑的整体功能。突触无法正常维持被认为会导致与年龄相关的认知能力下降，以及许多神经退行性疾病（如阿尔茨海默病）的病理。了解突触维持的机制可能会导致新的治疗方法，以减少突触损失，并可能确定与年龄和疾病相关的神经变性的危险因素。最近的研究已经确定了一种涉及精氨酸酪氨酸激酶的途径，该途径对突触和树突的维持至关重要。该项目的总体目标是确定哪些上游信号调节突触中的Arg活性，并确定这些信号对突触和树突稳定性的影响。先前在非神经元细胞中的研究表明，整合素是细胞外基质成分的受体，通过Arg发出信号来协调粘附和细胞骨架动力学。该项目将验证整合素/精氨酸相互作用促进体内突触稳定性的假设。将通过电子显微镜对不同年龄的arg和整合素1突变小鼠杂交后的海马突触进行量化。由于Arg活性也调节树突的稳定性，因此将通过染色填充活海马神经元来重建突变小鼠的树突乔木。本提案中概述的实验还将通过生物化学测量整合素1突变小鼠中已知精氨酸底物的相对活性来确定整合素是否通过精氨酸激酶发出信号。最后，本项目旨在通过一项新的目标识别任务，通过测量突变小鼠的整体海马功能，确定推定的整合素/精氨酸相互作用的行为相关性。通过遗传、生化和行为技术的互补使用，本项目旨在识别和表征促进突触和树突维持的整合素依赖的信号级联。这条研究路线的长期目标是充分了解体内稳定突触的机制。