Tools for manipulating protein condensates at the synapse

用于操纵突触处蛋白质凝聚物的工具

• 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
• 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

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.

不同的神经功能是由被称为凝聚物的浓缩生物分子组装驱动的。为