Role of Stress Granule Protein Aggregation in Axon Regeneration

应激颗粒蛋白聚集在轴突再生中的作用

• 批准号: 10030563
• 负责人: JEFFERY L TWISS
• 金额: $ 57.54万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10030563
• 关键词: Acute; Address; Adult; Affect; Attenuated; Automobile Driving; Axon; Axotomy; Binding; Biological; Cells; Chronic; Clinical; Communities; Complex; Cytoplasmic Granules; Data; FRAP1 gene; G3BP1 gene; Genetic Translation; Growth; Growth Associated Protein 43; Hour; Human; Importins; In Vitro; Individual; Injury; Knowledge; Lesion; Literature; Messenger RNA; Molecular; Motor; Natural regeneration; Nerve; Nerve Regeneration; Neuraxis; Neurons; Neurosciences; Pathway interactions; Peptides; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Permeability; Phosphorylation; Phosphotransferases; Physiological; Population; Protein Biosynthesis; Proteins; Publishing; RNA; RNA, Messenger, Stored; Regulation; Reporting; Research; Role; Sensory; Signal Transduction; Solid; Specificity; Spinal Cord; Spinal cord injury; Tertiary Protein Structure; Testing; Therapeutic; Time; Tissues; Translating; Translational Activation; Translations; Viral; Work; axon growth; axon injury; axon regeneration; calreticulin; casein kinase; clinically relevant; cohort; in vivo; injured; injury and repair; insight; knock-down; nerve injury; neuromechanism; novel therapeutic intervention; overexpression; programs; protein aggregation; recruit; regenerative; reinnervation; relating to nervous system; repaired; response to injury; stress granule; tool

Peripheral nerves spontaneously regenerate but the axon growth rate is abysmally slow, such that complete functional reinnervation of targets is rarely achieved in humans. Axon regeneration in the central nervous system is even worse, such that individuals with spinal cord injury (SCI) almost invariably have permanent lose of sensory and motor functions below the level of the lesion. There is a pressing need to accelerate axon regeneration in the peripheral nervous system and increase axon regeneration in the central nervous system. Our research program focuses on axon intrinsic mechanisms of regeneration. Intra-axonally synthesized proteins support axon growth in developing neurons. We have shown that PNS neurons retain the capacity to synthesize proteins in their axons and these proteins support growth of injured axons. Axons of cultured neurons contain thousands of mRNAs – and several lines of evidence point to complex populations of mRNAs in CNS axons in vivo and spinal cord axons contain mRNAs and translational machinery when encouraged to regenerate with permissive substrates. Despite remarkable advances since the early 2000’s, the molecular mechanisms that determine when and where a specific mRNA is translated in axons remain largely unknown. This level of regulation is critical for regulating axon growth capacity. We have shown that mRNAs are stored in PNS axons in RNA-protein aggregates that contain the stress granule protein G3BP1. G3BP1 protein can drive stress granule aggregation, and G3BP1 phosphorylation blocks stress granule assembly. Unlike the classically defined stress granule, axonal G3PB1 protein shows aggregation in uninjured/functioning PNS axons. These axonal G3BP1 aggregates rapidly increase after axotomy, but decrease to below basal levels shortly thereafter with a corresponding increase in phosphorylated G3BP1. G3BP1 binds to mRNAs in axons and attenuates their translation. We have discovered exogenous agents and endogenous signals that trigger disassembly of axonal G3BP1 aggregates. The exogenous agents specifically increase axonal protein synthesis and accelerate axon growth rates in vitro and in vivo. These observations have led us to hypothesize that physiological aggregation of stress granule proteins in axons attenuates axon growth in the injured PNS and CNS by blocking translation of an axonal mRNA cohort. We will test this hypothesis with the following specific aims: Aim 1 – Promotion of axon growth by inhibition of G3BP1 function. Aim 2 – Endogenous mechanisms for axonal G3BP1 aggregate disassembly. Aim 3 – Mechanisms driving axon growth upon disassembly of axonal G3BP1 aggregates. Functional roles for axonal translation have now come to light and we have solid in vivo evidence that this mechanism can be targeted to accelerate axon growth after acute peripheral nerve injury. Completion of the proposed research will bring new insight into mechanisms for temporal regulation of axonal mRNA translation in axon injury & regeneration and uncover new therapeutic strategies for neural repair.

周围神经自发再生，但轴突生长速度极慢，因此