GABARAP介导神经支架蛋白ARMS细胞膜转运的分子机理研究

神经系统的精准发育过程依赖于多种神经营养因子信号的协同调控，神经支架蛋白ARMS作为多种神经营养因子受体的共同下游底物，能整合协调多种营养刺激信号，促进神经元的发育和生长。ARMS作为跨膜蛋白，在神经细胞膜上的精确定位对神经营养刺激信号的整合与传递具有重要调控作用，其膜分布的动态平衡的破坏与诸多神经发育疾病如智障、脑瘫等密切相关。然而，调控ARMS膜定位的分子机理还不甚清楚。本项目计划采用多种生物学研究方法，围绕ARMS与其特异性结合蛋白GABARAP之间的相互作用及功能调控展开系统研究。项目将详细研究ARMS-GABARAP复合物的相互作用机制，解析蛋白复合物的三维结构，并探索GABARAP在调控ARMS细胞膜定位及动态转运过程中的功能。研究结果将为深入理解ARMS在神经信号转导过程中的作用机制提供分子与功能基础，并为与之功能异常相关的神经发育疾病的发病机理的解析及治疗奠定理论基础。

The precise development of the nervous system relies on the co-stimulation of multiple neurotrophic signaling cascades. ARMS, as a common downstream substrate of multiple neurotrophin receptors, can coordinate and integrate multiple nutrient stimulation signals, thereby adjusting their signaling outcome that can regulate multiple neuronal functions. The precise membrane localization of ARMS is essential for the coordination and integration of several trophic stimuli, and dysfunction of trafficking and localization of ARMS to cell membranes is clinically associated with severe psychiatric disorders in humans, including intellectual disability and cerebral palsy. However, the molecular mechanisms underlying the dynamic trafficking and localization of ARMS to cell membranes remain to be elucidated. In this research proposal, we will combine multidisciplinary approaches to elucidate the molecular mechanisms underlying the assembly and regulation of ARMS-GABARAP complex, to uncover the functions of GABRAP on regulating the dynamic trafficking of ARMS. The research will provide a molecular basis for an in-depth understanding of the trafficking and localization of ARMS to cell membranes, which will facilitate subsequent potential drug development and medical treatments of relevant neurodevelopmental disease research.