S1P-S1PR1 in bidirectional Neuron-Astrocyte communications

S1P-S1PR1 双向神经元-星形胶质细胞通讯

• 批准号: 10586618
• 负责人: Sandeep Kumar Singh
• 金额: $ 41.38万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-27 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586618
• 关键词: Astrocytes; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Pathology; Calcium; Communication; Coupled; Data; Development; Drug Targeting; Excitatory Synapse; GTP-Binding Proteins; Glutamates; Glypican; Goals; Homeostasis; In Vitro; Knock-out; Knowledge; Link; Mediating; Metabolic; Molecular; Morphogenesis; Morphology; Mus; Neuraxis; Neuroglia; Neurons; Process; Proteins; Publishing; Research; Role; Shapes; Signal Pathway; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; Structure; Synapses; Testing; Thrombospondins; base; hevin; in vivo; insight; nervous system disorder; neural circuit; neuronal circuitry; neuronal growth; neuronal survival; neuropathology; neurotransmission; novel; receptor; sphingosine 1-phosphate; sphingosine kinase; synaptic function; synaptogenesis; thrombospondin 4; vesicular glutamate transporter 2

Project Summary/ Abstract Though synapses are formed between neurons, these structures are contacted with, ensheathed, and regulated by astrocytes. Period of neuronal synaptic connectivity and that of astrocyte maturation overlaps in developing brain. Neuronal signals instruct astrocyte differentiation and morphological maturation whereas astrocytes provide metabolic and trophic factors to support neuronal survival and growth. However, molecular mechanisms and signals that regulate neuron-astrocyte interactions and their role in neuronal circuit assembly and functions are largely unknown. We and others have previously shown that astrocytes modulate specific neural circuit formation, function and plasticity by several secreted proteins including hevin (SPARCL1), thrombospondins (TSPs), glypicans and norrin. While hevin is needed for assembly and plasticity of VGlut2+ (vesicular glutamate transporter 2) thalamocortical connections, TSPs facilitate VGlut1+ synapse formation. Intriguingly, expression of these synaptogenic proteins is developmentally regulated and are also altered in brain pathologies. Although a significant amount of research has been done to identify the neuronal receptors and mechanism of synapse formation by astrocyte-secreted synaptogenic factors SPARCL1 and TSPs, we do not know the signals and mechanisms that regulate their expression in astrocytes. We have recently found that neuronal contact stimulates expression of SPARCL1 and TSP4 via Sphingosine- 1-Phosphate (S1P)-S1P Receptor 1 (S1PR1). We also found that S1PR1 is primarily expressed by astrocytes and is localized to the fine astrocytic processes near and around the synapses and drives astrocyte morphological complexity and morphogenesis. Although, S1P-S1PR signaling is a drug target for many neurological disorders, its fundamental role in neuron-glia interactions and neuronal circuit assembly is not known. Our proposed studies will provide novel insight into the neuron-astrocyte bidirectional communication through S1P-S1PR1 axis in establishing synaptic connectivity and functions. Our detailed mechanistic studies will identify new signaling pathway downstream of S1P-S1PR1 axis in regulating calcium dynamics, glutamate sensing and expression of SPARCL1 and TSP4 in astrocytes. These studies will also advance our knowledge of how neurons regulate astrocyte development, morphogenesis and function. Moreover, these studies will decipher the mechanistic link between levels of S1P and the expression of SPARCL1 and TSP4 and clarify on the fundamental role of S1P/S1PR1 axis in the developing and diseased brain. This proposal thus is poised to provide novel mechanisms of targeting S1P/S1PR1 axis in alleviating neuropathologies.

项目概要/摘要 虽然突触是在神经元之间形成的，但这些结构是接触、包裹和包裹的。 受星形胶质细胞调节。神经元突触连接的时期和星形胶质细胞成熟的时期重叠 正在发育的大脑。神经元信号指示星形胶质细胞分化和形态成熟，而 星形胶质细胞提供代谢和营养因子来支持神经元的存活和生长。然而，分子 调节神经元-星形胶质细胞相互作用的机制和信号及其在神经元回路组装中的作用 和功能很大程度上是未知的。我们和其他人之前已经证明星形胶质细胞调节特定的 几种分泌蛋白的神经回路形成、功能和可塑性，包括 hevin (SPARCL1)、 血小板反应蛋白 (TSP)、磷脂酰肌醇蛋白聚糖和诺里蛋白。虽然 VGlut2+ 的组装和可塑性需要 hevin （囊泡谷氨酸转运蛋白 2）丘脑皮质连接，TSP 促进 VGlut1+ 突触形成。 有趣的是，这些突触蛋白的表达受到发育调节，并且在大脑中也发生改变 病理学。尽管已经进行了大量研究来识别神经元受体和 星形胶质细胞分泌的突触因子 SPARCL1 和 TSP 形成突触的机制，我们不知道 了解调节星形胶质细胞表达的信号和机制。 我们最近发现神经元接触通过鞘氨醇刺激 SPARCL1 和 TSP4 的表达 1-磷酸盐 (S1P)-S1P 受体 1 (S1PR1)。我们还发现S1PR1主要由星形胶质细胞表达 定位于突触附近和周围的精细星形胶质细胞过程并驱动星形胶质细胞 形态复杂性和形态发生。尽管 S1P-S1PR 信号传导是许多药物的靶点 神经系统疾病，其在神经元-胶质细胞相互作用和神经元回路组装中的基本作用并不 已知。我们提出的研究将为神经元-星形胶质细胞双向通信提供新的见解 通过 S1P-S1PR1 轴建立突触连接和功能。我们详细的机制研究 将确定 S1P-S1PR1 轴下游调节钙动力学、谷氨酸的新信号通路 星形胶质细胞中 SPARCL1 和 TSP4 的传感和表达。这些研究也将增进我们的知识 研究神经元如何调节星形胶质细胞的发育、形态发生和功能。此外，这些研究将 破译 S1P 水平与 SPARCL1 和 TSP4 表达之间的机制联系，并阐明 S1P/S1PR1 轴在发育和患病大脑中的基本作用。因此，这项提议旨在 提供靶向 S1P/S1PR1 轴以减轻神经病理学的新机制。