Function and regulation of heterotrimeric G proteins in ciliogenesis and pathobiology of neurodevelopmental disorders

异源三聚体 G 蛋白在纤毛发生和神经发育障碍病理学中的功能和调节

• 批准号: 10651317
• 负责人: Inna Nechipurenko
• 金额: $ 36.4万
• 依托单位: WORCESTER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651317
• 关键词: Afferent Neurons; Anatomy; Behavioral; Biological Assay; Biomedical Research; Caenorhabditis elegans; Cell physiology; Cells; Cilia; Data; Defect; Development; Developmental Biology; Experimental Models; Foundations; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GNAI1 gene; GTP-Binding Protein alpha Subunits; GTP-Binding Proteins; Genes; Genetic; Genetic Diseases; Goals; Heterotrimeric GTP-Binding Proteins; Human; Image; Impairment; Intellectual functioning disability; Investigation; Knowledge; Lead; Literature; Mammals; Maps; Mediating; Membrane; Modeling; Molecular; Morphogenesis; Morphology; Motor; Mutation; Nervous System; Neuroanatomy; Neurodevelopmental Disorder; Neurologic Deficit; Neurons; Orthologous Gene; Outcome; Pathway interactions; Patients; Phenotype; Property; Protein Subunits; Proteins; Proteomics; Public Health; Publishing; Regulation; Research; Role; Sensory; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Surface; Testing; Therapeutic; Work; brain abnormalities; candidate identification; career; cilium biogenesis; genome editing; in vivo; innovation; insight; mutant; neuron development; neuropathology; novel; novel therapeutics; protein function; skills; therapeutic target; undergraduate student

PROJECT SUMMARY Many components of G-protein-coupled receptor (GPCR) signaling including heterotrimeric G (abg) proteins localize to primary cilia and modulate their morphology. Although cilia defects and dysregulated G protein signaling are associated with neurodevelopmental disorders (NDDs), the mechanisms by which G proteins regulate cilia morphogenesis or the extent to which disruption of ciliary Ga signaling contributes to NDDs remain largely unknown. The overall objective for this proposal is to define the molecular mechanisms by which RIC-8 – a highly conserved GPCR-independent activator of Ga proteins – shapes cilia morphology in sensory neurons. The overarching hypothesis for this application is that RIC-8 is dynamically trafficked to sensory cilia and controls ciliogenesis by potentiating Ga signaling. This hypothesis will be tested by pursuing two specific aims. Under the first aim, in vivo protein interaction assays and genome editing approaches will be used to mechanistically define the functional role of the RIC-8-Gai/o axis in controlling cilia morphogenesis. For the second aim, a synergistic approach comprised of genetic, imaging and in vivo proteomic approaches will be applied to identify molecular regulators of RIC-8 ciliary transport and function in sensory neurons. The proposed research is innovative because it uses a comprehensive approach to define a novel cellular function of RIC-8- Gai/o signaling in neuronal development. The proposed research is significant because it is expected to establish a strong scientific framework for investigations into the molecular composition and functions of the ciliary RIC-8- Gai/o signaling network(s) in C. elegans and vertebrate models and to determine how altered Ga-protein signaling may contribute to neurodevelopmental disorders.

项目概要 G 蛋白偶联受体 (GPCR) 信号传导的许多成分，包括异三聚体 G (abg) 尽管纤毛缺陷和 G 失调，但蛋白质定位于初级纤毛并调节其形态。 蛋白质信号传导与神经发育障碍 (NDD) 相关，G 的机制是 蛋白质调节纤毛形态发生或纤毛 Ga 信号传导破坏对 NDD 的影响程度 该提案的总体目标仍然很大程度上未知。 RIC-8——一种高度保守的、不依赖于 GPCR 的 Ga 蛋白激活剂——在感觉中塑造纤毛形态 该应用的总体假设是 RIC-8 动态运输至感觉纤毛。 并通过增强 Ga 信号传导来控制纤毛发生。这一假设将通过两个特定的方法进行检验。 在第一个目标下，体内蛋白质相互作用测定和基因组编辑方法将用于 机械地定义 RIC-8-Gai/o 轴在控制纤毛形态发生中的功能作用。 第二个目标是采用由遗传、成像和体内蛋白质组学方法组成的协同方法 用于识别感觉神经元中 RIC-8 纤毛运输和功能的分子调节剂。 研究具有创新性，因为它使用综合方法来定义 RIC-8 的新颖细胞功能 神经发育中的 Gai/o 信号传导具有重要意义，因为它有望建立。 一个强大的科学框架，用于研究睫状体 RIC-8- 的分子组成和功能 线虫和脊椎动物模型中的 Gai/o 信号网络并确定 Ga 蛋白信号如何改变 可能会导致神经发育障碍。