Tools for manipulating protein condensates at the synapse

用于操纵突触处蛋白质凝聚物的工具

基本信息

批准号：
10725576
负责人：
Matthew J Kennedy
金额：
$ 42.9万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-08-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725576
关键词：
Acute Aging Binding Biochemical Biological Biological Process Biophysics Brain Brain Diseases Cells Cellular Structures Chemicals Cognition Disorders Development Disease model Engineering Gel Genetic Goals In Situ In Vitro Internet Lead Ligands Light Liquid substance Methods Modeling Nerve Degeneration Nervous System Neurons Neurophysiology - biologic function Neurotransmitter Receptor Output Phase Physical condensation Positioning Attribute Process Property Proteins Rest Role Scaffolding Protein Signal Transduction Signaling Molecule Structure Substance Use Disorder Synapses Synaptic Transmission Synaptic plasticity System Testing Time Viscosity Work addiction biophysical properties density experimental study fluidity nano neural circuit neuron development neuropsychiatric disorder novel strategies postsynaptic protein purification receptor reconstitution recruit remote control scaffold small molecule solid state synaptic function synaptogenesis tool trafficking

项目摘要

Diverse neural functions are driven by concentrated biomolecular assemblies known as condensates. For example, the postsynaptic density, a structure that anchors neurotransmitter receptors and signaling molecules at the synapse, is thought to form a condensate through a phase-separation process involving multiple highly- networked scaffold molecules. How do the biophysical and material properties of the postsynaptic condensate contribute to synaptic function and plasticity? This project will develop and extend methods that allow inducible formation and/or disruption of biomolecular condensates, applying them in neurons to modulate the material properties of the postsynaptic density while simultaneously assessing synapse structure and function. Aim 1 will develop and apply tools to rapidly increase the rigidity of the postsynaptic density and assess the functional consequences on synaptic structure and plasticity. Aim 2 will focus on methods to inducibly increase the fluidity of the postsynaptic density, reducing the valency of specific scaffold molecules involved in condensate formation. This work will develop general-use tools for manipulating biomolecular condensates throughout the nervous system, with implications for neuronal development, neuropsychiatric diseases, addiction and other brain disorders.

多种神经功能由称为冷凝物的浓缩生物分子组件驱动。为了例如，突触后密度，一种锚定神经递质受体和信号分子的结构在突触时，人们认为通过涉及多个高度高度的相分开过程形成冷凝物网络支架分子。突触后冷凝物的生物物理和材料特性如何有助于突触功能和可塑性？该项目将开发并扩展允许诱导的方法生物分子冷凝物的形成和/或破坏，将它们涂在神经元中以调节材料突触后密度的特性，同时评估突触结构和功能。目标1 将开发和应用工具以快速提高突触后密度的刚度并评估功能突触结构和可塑性的后果。 AIM 2将重点放在诱导的方法上的方法上突触后密度，降低了与冷凝水有关的特定支架分子的价值形成。这项工作将开发一种通用工具，用于操纵整个过程中的生物分子冷凝物神经系统，对神经元发展，神经精神疾病，成瘾和其他脑疾病。