Elucidating the Trophic Support of Long Axons by Metabolic Signaling in Oligodendrocytes

通过少突胶质细胞代谢信号阐明长轴突的营养支持

基本信息

批准号：
10782630
负责人：
Bogdan Beirowski
金额：
$ 37.49万
依托单位：
OHIO STATE UNIVERSITY
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：
2023-02-09 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10782630
关键词：
5&apos -AMP-activated protein kinase Adult Alzheimer&apos s Disease Attenuated Axon Biological Central Nervous System Cessation of life Data Defect Deterioration Diameter Disease Electrophysiology (science)Energy Metabolism Etiology Failure Fiber GLC2 protein Genetic Glean Glucose Health Promotion Homeostasis Impairment Individual Intoxication Life Expectancy Metabolic Metabolic Pathway Metabolism Microfluidic Microchips Mitochondria Modeling Molecular Multiple Sclerosis Mutant Strains Mice Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurologic Oligodendroglia Optic Nerve Output Pathway interactions Phenotype Phosphorylation Phosphotransferases Play Regulation Role STK11 gene Schwann Cells Secondary to Signal Pathway Signal Transduction Structure Therapeutic Work axon injury axonal degeneration deprivation disability imaging modality in vivo interdisciplinary approach lipid metabolism liver ablation metabolome mitochondrial metabolism mouse model mutant myelination neural circuit new therapeutic target novel preservation sensor therapeutic target tool upstream kinase white matter

项目摘要

The fundamenal neuroscientific question as to how myelinating glia promote the health of long axons is greatly understudied. Axons are a particularly vulnerable component of neural circuits that are irreversibly damaged in early stages of many debilitating neurodegenerative conditions such as Multiple sclerosis and Alzheimers’ disease. The mechanisms underlying glial contributions to axonal injury are only pooly understood. Oligodendrocytes (OLGs), the myelinating glia of the central nervous system, stabilize axonal integrity by poorly understood trophic mechanisms. Current models suggest that glial metabolism is critical for this support function, and disrupted metabolic exchange between OLGs and axons, or metabolic deficits in OLGs may lead to axonal degeneration. In support, we made the exciting discovery that the LKB1 (liver kinase B1) signaling pathway is a crucial metabolic regulator in OLGs, and the inactivation of LKB1 in these glia results in aberrant mitochondrial energy metabolism and progressive degeneration of axons. Remarkably, such non-cell-autonomous axon degeneration is not preceded by changes of OLG structure and myelination, indicating that it occurs secondary to glial metabolic perturbation. These discoveries lead us to hypothesize that LKB1 and its downstream metabolic effectors, most notably those regulating mitochondrial metabolism in OLGs, are integral to the trophic support mechanisms for axons. Using manipulation of LKB1 signaling as an experimental tool to change glial metabolism with no impact on other biological outputs of OLGs, here we implement a multidisciplinary approach that will afford us the unique opportunity to pinpoint metabolic alterations in OLGs that disrupt the support of axons. In this context we will also investigate whether axons degenerate as a consequence of energetic deprivation, or metabolic poisoining. Together, this will provide valuable data to elucidate which downstream components of the LKB1-dependent metabolic signaling network in OLGs are fundamentally important for axon integrity. The proposed efforts may open the door to the identification of unexpected metabolic components in OLGs that are essential for axon support. Manipulation of these components will have the potential to promote axon integrity in neurodegenerative diseases. Because glial and metabolic abnormalities associated with axon degeneration can be observed in many neurodegenerative conditions, this approach has the potential for wide-ranging therapeutic impact.

关于髓鞘神经胶质细胞如何促进长期健康的基本神经科学问题轴突是神经回路中特别脆弱的组成部分，目前的研究还很少。在许多使人衰弱的神经退行性疾病的早期阶段受到不可逆转的损害例如多发性硬化症和阿尔茨海默病。少突胶质细胞（OLG）对轴突损伤的作用目前还知之甚少。中枢神经系统的髓鞘神经胶质细胞，通过知之甚少的方式稳定轴突完整性目前的模型表明神经胶质代谢对于这种支持至关重要。功能，并扰乱 OLG 和轴突之间的代谢交换，或代谢缺陷 OLGs 可能导致轴突变性，我们做出了令人兴奋的发现，即 LKB1。（肝激酶 B1）信号通路是 OLG 中重要的代谢调节因子，其失活这些神经胶质细胞中 LKB1 的缺失导致线粒体能量代谢异常和进行性进展值得注意的是，这种非细胞自主的轴突变性不是。先有 OLG 结构和髓鞘形成的变化，表明它继发于这些发现使我们认识到 LKB1 及其相关性。下游代谢效应器，最显着的是那些调节线粒体代谢的效应器 OLG 是轴突营养支持机制不可或缺的一部分。信号传导作为改变神经胶质代谢的实验工具，而不影响其他生物 OLG 的产出，在这里我们实施多学科方法，这将为我们提供独特的有机会查明 OLG 中破坏轴突支持的代谢变化。我们还将研究轴突是否因能量消耗而退化总之，这将为阐明哪些因素提供有价值的数据。 OLG 中 LKB1 依赖性代谢信号网络的下游组件是对于轴突的完整性至关重要。所提出的努力可能会打开大门。鉴定 OLG 中意想不到的代谢成分，这些成分对轴突支持至关重要。对这些组件的操纵将有可能促进轴突的完整性因为神经退行性疾病与轴突相关的神经胶质和代谢异常。在许多神经退行性疾病中都可以观察到退行性变，这种方法具有具有广泛治疗影响的潜力。