Regulation Of Plasma Membrane Properties in Excitable Cells by Wnt Signaling

Wnt 信号传导调节可兴奋细胞的质膜特性

• 批准号: 2224262
• 负责人: Andrés Barría
• 金额: $ 100万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2224262&HistoricalAwards=false
• 关键词: Regulation; Plasma; Membrane; Properties; Excitable

Excitable cells produce, amplify, and propagate electrical signals. In the nervous system, these cells carry the information that allows multicellular organisms to coordinate a range of sensory and motor functions, from producing simple escape responses to orchestrating sophisticated learning and cognitive behaviors. This project investigates fundamental molecular and cellular properties of neurons regulated by Wnt signaling, a highly conserved cellular signaling pathway that regulates animal embryonic development but is also present in the mature central nervous system (where its function is still poorly understood). Preliminary data suggests that Wnt signaling in adults enables nerve cells to better synchronize their activity, a necessary step for proper information processing, memory formation, and cognition. Using a novel and systematic approach combining fluorescence imaging, electrophysiology, biochemistry, and molecular biology, this project will elucidate exactly how Wnt signaling regulates adult neuronal properties. This knowledge will further scientific understanding about how anatomically static neural circuits can adjust the responses of their cellular components to adaptively respond to changes in incoming stimuli. In addition, this project will offer training opportunities for students from underrepresented and disadvantaged communities in modern neuroscience techniques, and to participate in career development and networking events that will bolster their abilities to pursue careers in science and technology. The principal investigator will also carry out a number of activities that will contribute to generating a more diverse, equitable, and inclusive environment at the sponsoring institution, and in his own field of research. Wnt signaling is a highly conserved signal transduction pathway that regulates embryonic development of metazoans and is also present in the mature central nervous system of mammals, where its function is poorly understood. We have described a novel non-canonical Wnt signaling cascade that regulates trafficking of NMDA-type glutamate receptors (NMDARs) affecting synaptic plasticity, a cellular and molecular model of memory formation. Our most recent studies show that Wnt signaling in addition alters two key intrinsic properties of neurons: the resting membrane potential and the preferred resonant frequency that gives rise to coordinated oscillatory behaviors in cellular circuits. In a logical extension of our previous work, this project examines Wnt regulation of key plasma membrane ionic channels that shape cellular resonance and the metabolism of membrane lipids involved in such regulation. We hypothesize that Wnt signaling modulates intrinsic properties of cell membranes via modulation of the metabolism of plasma membrane lipids and key ion channels that underlie cellular resonance. We will: 1) identify the ion channels regulated by Wnt signaling that are involved in modulating intrinsic properties of neurons, and 2) establish whether Wnt signaling regulates distribution and availability of plasma membrane phospholipids that determine biophysical properties of membrane ion channel activities. The new information produced by this project is expected to lead to a greater understanding of how neural circuits adaptively regulate the properties of their constituent cells to help organisms cope with the constantly changing world around them.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.

可兴奋细胞产生、放大和传播电信号。在神经系统中，这些细胞携带着信息，使多细胞生物能够协调一系列感觉和运动功能，从产生简单的逃避反应到协调复杂的学习和认知行为。该项目研究了受Wnt信号调控的神经元的基本分子和细胞特性，Wnt信号是一种高度保守的细胞信号通路，调节动物胚胎发育，但也存在于成熟的中枢神经系统中（其功能仍知之甚少）。初步数据表明，成人的Wnt信号使神经细胞的活动更好地同步，这是正确的信息处理、记忆形成和认知的必要步骤。利用一种新颖而系统的方法，结合荧光成像、电生理学、生物化学和分子生物学，该项目将阐明Wnt信号如何调节成年神经元的特性。这些知识将进一步科学地理解解剖静态神经回路如何调节其细胞成分的反应，以适应传入刺激的变化。此外，该项目将为来自代表性不足和弱势群体的学生提供现代神经科学技术方面的培训机会，并参与职业发展和网络活动，以增强他们在科学和技术领域的职业发展能力。首席研究员还将开展一系列活动，有助于在赞助机构和他自己的研究领域创造一个更加多样化、公平和包容的环境。Wnt信号是一种高度保守的信号转导通路，它调节后生动物的胚胎发育，也存在于哺乳动物成熟的中枢神经系统中，但其功能尚不清楚。我们描述了一种新的非规范Wnt信号级联，它调节影响突触可塑性的nmda型谷氨酸受体（NMDARs）的运输，这是记忆形成的细胞和分子模型。我们最近的研究表明，Wnt信号还改变了神经元的两个关键内在特性：静息膜电位和在细胞电路中引起协调振荡行为的首选共振频率。在我们之前工作的逻辑延伸中，该项目研究了Wnt对形成细胞共振的关键质膜离子通道的调节以及参与这种调节的膜脂代谢。我们假设Wnt信号通过调节细胞膜脂质代谢和细胞共振基础上的关键离子通道来调节细胞膜的内在特性。我们将：1)确定参与调节神经元内在特性的Wnt信号调节的离子通道，2)确定Wnt信号是否调节决定膜离子通道活性生物物理特性的质膜磷脂的分布和可用性。该项目产生的新信息有望使人们更好地了解神经回路如何自适应地调节其组成细胞的特性，以帮助生物体应对周围不断变化的世界。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。