Integrin Signaling Through Arg Kinase Regulates Synapse and Dendrite Stabilizatio

描述（由申请人提供）：通过Arg激酶的整合素信号传导调节突触和树突稳定。人类大脑中的突触必须在较长的时间内积极维持，以确保神经元传输和整体大脑功能的功效。不能正确维持突触被认为是导致与年龄相关的认知能力下降和许多神经退行性疾病如阿尔茨海默病的病理学原因。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，并可能确定年龄和疾病相关的神经退行性变的危险因素。最近的研究已经确定了一个途径，涉及精氨酸酪氨酸激酶是必不可少的突触和树突的维护。这个项目的总体目标是确定哪些上游信号调节突触的精氨酸活性，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已经证明，整合素是细胞外基质成分的受体，通过Arg信号来协调粘附和细胞骨架动力学。该项目将测试整合素/精氨酸相互作用促进体内突触稳定性的假设。将通过电子显微镜在不同年龄的arg和整合素1突变小鼠之间的交叉中定量海马突触。由于Arg活性也调节树突稳定性，因此将通过染料填充活海马神经元在突变小鼠中重建树突乔木。本提案中概述的实验还将通过生物化学测量整联蛋白1突变小鼠中已知Arg底物的相对活性来确定整联蛋白是否通过Arg激酶发出信号。最后，本项目的目的是通过一种新的物体识别任务来测量突变小鼠的整体海马功能，以确定推定的整合素/精氨酸相互作用的行为相关性。通过遗传学、生物化学和行为学技术的互补使用，该项目旨在识别和表征促进突触和树突维持的整合素依赖性信号级联。这一系列研究的长期目标是充分了解体内稳定突触的机制。 公共卫生相关性：通过精氨酸激酶的整合素信号调节突触和树突稳定性年龄和疾病相关的神经退行性疾病在世界范围内造成了巨大的个人、社会和经济负担。由于作为神经元之间的连接的突触的损失是许多形式的神经变性中的常见病理，因此人工稳定突触的治疗性干预可以具有广泛的应用。该项目将描述一种新的生物化学机制，促进突触稳定性，以确定新的治疗靶点。

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.