Signaling mechanism for synapse formation and function regulated by the release of GPI-anchored synaptogenic factors from astrocytes

星形胶质细胞释放 GPI 锚定的突触因子调节突触形成和功能的信号机制

基本信息

批准号：
10188651
负责人：
Sung Jin Park
金额：
$ 33.36万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188651
关键词：
Astrocytes Brain Bypass Cell Surface Proteins Cell membrane Cleaved cell Communication Conditioned Culture Media Data Defect Dendritic Spines Development Diffuse Disease Drug Targeting Electrophysiology (science)Enzymes Exhibits GPI Membrane Anchors Genetic Glutamate Receptor Glycosylphosphatidylinositols Glypican Impairment Intellectual functioning disability Knockout Mice Lead Lipids Location Mediating Membrane Molecular Nervous System Physiology Nervous system structure Neuroglia Neurons Play Protein Isoforms Proteins Research Role Schizophrenia Signal Pathway Signal Transduction Signaling Molecule Structure Surface Synapses Synaptic Transmission Testing Therapeutic Intervention Vertebrates autism spectrum disorder base communication aid design exosome extracellular extracellular vesicles glycerophosphodiester phosphodiesterase high throughput screening in vivo in vivo evaluation intercellular communication mouse model nervous system disorder novel novel therapeutics synaptic function synaptogenesis vesicular release

项目摘要

Dynamic interplay between neurons and glia is critical to establish the proper structure and function of the nervous system. In particular, astrocytes are powerful regulators of the multiple steps of synapse development and function. However, we lack mechanistic understanding of how signaling molecules are delivered from astrocytes to neurons to regulate the synaptogenesis. In this proposal, we present evidence that GDE3, the major regulator of the glycosylphosphatidylinositol (GPI)-anchored proteins on the astrocyte surface, is required for synapse development and function. GDE3 facilitates the release of GPI-anchored proteins from astrocytes in two modes: GPI-shedding and extracellular vesicular release. In this proposal, we will define the release mechanism of the active form of synaptogenic factors and downstream effectors of GDE3. Importantly, we will determine the specific role of GPI-anchorage in synapse development and function in the developing brain. Our results will reveal a novel signaling mechanism of astrocyte-neuron communications and aid the design of alternative therapeutic interventions for diseases caused by synaptogenic defects.

神经元和神经胶质细胞之间的动态相互作用对于建立神经元的正确结构和功能至关重要神经系统。特别是，星形胶质细胞是突触发育多个步骤的强大调节者和功能。然而，我们对信号分子如何传递的机制缺乏了解。星形胶质细胞到神经元来调节突触发生。在本提案中，我们提供了 GDE3 的证据，即星形胶质细胞表面糖基磷脂酰肌醇 (GPI) 锚定蛋白的主要调节因子是突触发育和功能所需的。 GDE3 促进 GPI 锚定蛋白的释放星形胶质细胞有两种模式：GPI 脱落和细胞外囊泡释放。在本提案中，我们将定义 GDE3突触因子活性形式和下游效应子的释放机制。重要的是，我们将确定 GPI 锚定在突触发育和发育中的功能中的具体作用脑。我们的结果将揭示星形胶质细胞-神经元通讯的一种新的信号机制，并帮助针对突触缺陷引起的疾病设计替代治疗干预措施。