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The role of PI3Kg signaling in microglial dynamics and experience dependent synaptic plasticity

PI3Kg 信号在小胶质细胞动力学和经验依赖性突触可塑性中的作用

基本信息

批准号：
10210217
负责人：
Brendan Steven Whitelaw
金额：
$ 5.1万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210217
关键词：
Acute Adenosine Triphosphate Affect Attention Behavior Brain Cells Chemotaxis Complement Complex Couples Cytoskeleton Data Development Disease Environment Functional disorder Future G-Protein-Coupled Receptors Genetic Goals Heart Diseases Immune In Vitro Inflammation Inflammatory Injury Investigation Knockout Mice Lead Malignant Neoplasms Mediating Mediator of activation protein Microglia Molecular Morphology Nerve Degeneration Nervous System Physiology Neuraxis Neuroglia Neuronal Plasticity Neurons Nucleotides Ocular Dominance Pathologic Pathway interactions Patients Phagocytosis Pharmacology Phosphatidylinositols Phosphotransferases Physiological Preparation Process Property Protein Isoforms Proteins Publishing Receptor Activation Regulation Role Scientist Shapes Signal Pathway Signal Transduction Signaling Protein Surveys Synapses Synaptic plasticity Testing Time Translating Work brain cell brain parenchyma career cell motility experience extracellular genetic manipulation in vivo in vivo Model insight nerve stem cell nervous system disorder neurogenesis neuron development neuropsychiatry receptor response

项目摘要

Project Summary: Microglia, in addition to their role as immune cells of the central nervous system (CNS), are critical players in the development and function of the CNS. Microglia are dynamic cells that interact extensively with neurons, allowing them to regulate neurogenesis, refine neuronal networks, and influence synaptic plasticity. The same properties that allow microglia to shape the development of the CNS may also lead to neurological disease if not properly regulated. The extracellular signals that mediate microglial dynamics and interactions with neurons are not well understood. Signaling through extracellular nucleotides has emerged as a key mechanism by which microglia sense and interact with their external environment. Specifically, the microglial P2Y12 receptor is crucial for microglial responsiveness to extracellular adenosine tri-phosphate (ATP) and mediates numerous microglial functions, including ATP-dependent chemotaxis, microglia-neuron interactions, and experience-dependent synaptic plasticity. However, little is known about the downstream signaling effectors that mediate these diverse actions of P2Y12. My preliminary data and previously published work suggest that P2Y12 activates phosphoinositide-3-kinase gamma (PI3Kγ), which in turn can activate the signaling pathways required for ATP- mediated microglial chemotaxis. In this role, PI3Kγ could translate localized extracellular ATP signals into directed microglial action and serve as a broad effector of P2Y12-dependent functions. In this proposal, I will test the hypothesis that microglial PI3Kγ mediates microglial ATP-dependent chemotaxis, microglial dynamics, and experience-dependent synaptic plasticity. In order to understand how PI3Kγ activation affects P2Y12-driven microglial behavior, I will first determine the role of PI3Kγ in directed microglial motility towards ATP, using in vitro, ex vivo, and in vivo approaches, and further dissect this molecular pathway, using a combination of pharmacological and genetic manipulations (Aim 1). In parallel, I will determine how genetic loss of microglial PI3Kγ affects microglial morphology, dynamics, and ocular dominance plastic in vivo, a process in which microglia are known to participate. These two lines of investigation will examine the molecular pathways underling distinct P2Y12-dependent microglia processes, and for the first time characterize the role of PI3Kγ in the unperturbed CNS. Uncovering these molecular mechanisms will be critical to understanding the role of microglia as mediators of neuronal function and their role in disease-related processes.

项目摘要：小神经胶质细胞除了作为中枢神经系统（CNS）的免疫细胞的作用之外，还是中枢神经系统（CNS）免疫系统中的关键参与者。 CNS的发育和功能。小胶质细胞是一种动态细胞，与神经元广泛相互作用，它们调节神经发生，改善神经网络，并影响突触可塑性。相同的性质小胶质细胞影响中枢神经系统的发育，如果不适当的话，监管.介导小胶质细胞动力学和与神经元相互作用的细胞外信号不太好明白通过细胞外核苷酸的信号传导已经成为小胶质细胞感知并与外部环境互动。具体来说，小胶质细胞P2 Y12受体对于小胶质细胞对细胞外三磷酸腺苷（ATP）的反应，并介导许多小胶质细胞功能，包括ATP依赖的趋化性，小胶质细胞-神经元相互作用，和经验依赖性突触可塑性然而，很少有人知道下游信号效应，介导这些不同的， P2 Y12的作用。我的初步数据和以前发表的工作表明，P2 Y12激活磷酸肌醇-3-激酶γ（PI 3 K γ），这反过来又可以激活ATP所需的信号通路。介导的小胶质细胞趋化性。在这一作用中，PI 3 K γ可以将局部的细胞外ATP信号翻译成指导小胶质细胞作用，并作为P2 Y12依赖性功能的广泛效应物。在这份提案中，我将检验小胶质细胞PI 3 K γ介导小胶质细胞ATP依赖性趋化性、小胶质细胞动力学和经验依赖的突触可塑性。为了了解PI 3 K γ激活如何影响P2 Y12驱动的为了研究小胶质细胞的行为，我将首先确定PI 3 K γ在定向小胶质细胞向ATP运动中的作用，体外，离体和体内方法，并进一步剖析这一分子途径，使用组合药理学和遗传操作（目的1）。与此同时，我将确定小胶质细胞的遗传丢失 PI 3 K γ影响体内小胶质细胞形态、动力学和眼优势可塑性，这是一个过程，已知小胶质细胞参与其中。这两条研究路线将研究在不同的P2 Y12依赖性小胶质细胞过程的基础上，并首次描述了PI 3 K γ在不受干扰的中枢神经系统揭示这些分子机制将是至关重要的理解的作用，小胶质细胞作为神经元功能的介质及其在疾病相关过程中的作用。