Wnt Signaling in the Mature Central Nervous System

成熟中枢神经系统中的 Wnt 信号传导

• 批准号: 1755004
• 负责人: Andrés Barría
• 金额: $ 120万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1755004&HistoricalAwards=false
• 关键词: Wnt; Signaling; Mature; Central; Nervous

Information transmission across synaptic connections between neurons is fundamental to brain functions, such as perception, action, and cognition, and changes in the strength of synaptic communication is widely believed to underlie learning and memory. Wnt signaling is a group of highly conserved biochemical signal transduction pathways known for their involvement in various embryonic processes. The presence of Wnt signaling elements in the mature brain suggests that Wnt signaling may also play a role in the regulation of brain functions in the adult. This project examines the role and mechanisms of action of Wnt signaling in the mature brain, from the receptors through which Wnt initiates signal transduction to the targets of the transduction process, such as proteins critically involved in synaptic communication and plasticity. The findings provide insights into how signaling pathways involved in embryonic development are re-deployed to effect lasting modifications in adult organisms. They also inform the development of treatments for conditions in which synaptic transmission is compromised. In addition, the project provides training opportunities for students and postdoctoral researchers from underrepresented groups, with the goal of increasing their participation in science professions.Wnt signaling is a highly conserved signal transduction mechanism that regulates embryonic development of metazoans; however, the sustained expression of Wnt signaling components in the mature central nervous system (CNS) of vertebrates suggests that Wnt signaling cascades might also play a part in regulating brain function beyond embryonic development. Recent findings by the investigator indicate that a non-canonical Wnt ligand upregulates synaptic currents mediated by NMDA-type glutamate receptors. This regulation requires Wnt receptor RoR2, an increase in intracellular Ca2+, and activation of PKC and JNK. The objectives of this project are to: (1) determine how the Wnt receptor RoR2 is activated and whether it is sufficient to initiate the signaling cascade leading to regulation of glutamatergic synaptic transmission, and (2) unravel the signaling cascade triggered by activation of RoR2 receptors. To achieve these objectives, a range of approaches are applied, including biochemical techniques, live fluorescence Förster resonance energy transfer (FRET), in some experiments combined with FRET based biosensors, Ca2+ imaging, and electrophysiology. Understanding how RoR2 signals in the mature CNS of vertebrates provides insight into Wnt signaling in general, contributes to better understanding of the regulation of synaptic plasticity, and ultimately offers proof-of-principle evidence for a general process by which biological mechanisms used early in an organism's life can be coopted in the mature organism for homeostatic processes or new biological functions. This project was co-funded by the Modulation Program in the Neural Systems Cluster in the Division of Integrative Organismal Systems, the Cellular Dynamics and Function Cluster in the Division of Molecular and Cellular Biosciences, and the Rules of Life Venture Fund in the Division of Emerging Frontiers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

通过神经元之间的突触连接的信息传输是大脑功能的基础，例如感知，动作和认知，并且突触通信强度的变化被广泛认为是学习和记忆的基础。Wnt信号转导是一组高度保守的生化信号转导途径，参与多种胚胎发育过程。成熟脑中Wnt信号元件的存在表明Wnt信号传导也可能在成人脑功能的调节中发挥作用。该项目研究了Wnt信号在成熟大脑中的作用和作用机制，从Wnt启动信号转导的受体到转导过程的靶点，如关键参与突触通讯和可塑性的蛋白质。这些发现提供了有关胚胎发育中涉及的信号通路如何重新部署以影响成年生物体的持久修饰的见解。它们还为开发突触传递受损的治疗方法提供了信息。此外，该项目还为来自代表性不足群体的学生和博士后研究人员提供培训机会，目标是增加他们对科学专业的参与。Wnt信号转导是一种高度保守的信号转导机制，调节后生动物的胚胎发育;但是，在此情况下，在成熟的中枢神经系统（CNS）中持续表达Wnt信号传导成分脊椎动物的研究表明，Wnt信号级联也可能在胚胎发育后调节大脑功能方面发挥作用。 研究者最近的发现表明，非经典Wnt配体上调NMDA型谷氨酸受体介导的突触电流。这种调节需要Wnt受体RoR 2、细胞内Ca 2+的增加以及PKC和JNK的激活。本项目的目的是：（1）确定Wnt受体RoR 2如何被激活，以及它是否足以启动信号级联反应，从而调节突触能突触传递，以及（2）解开RoR 2受体激活引发的信号级联反应。 为了实现这些目标，应用了一系列方法，包括生物化学技术，活荧光Förster共振能量转移（FRET），在一些实验中结合基于FRET的生物传感器，Ca 2+成像和电生理学。了解RoR 2信号在脊椎动物的成熟中枢神经系统中的作用提供了对Wnt信号传导的一般认识，有助于更好地理解突触可塑性的调节，并最终为生物体生命早期使用的生物学机制可以在成熟生物体中用于稳态过程或新的生物学功能的一般过程提供了原理性证据。该项目由综合有机系统部神经系统群的调制计划，分子和细胞生物科学部的细胞动力学和功能群，该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的评估被认为值得支持。影响审查标准。