Muscle building supplement HMB for remyelination

用于髓鞘再生的增肌补充剂 HMB

• 批准号: 10442389
• 负责人: KALIPADA PAHAN
• 金额: $ 39.25万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 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/10442389
• 关键词: Animal Model; Area; Axon; Binding; Brain; Clinical; Cuprizone; Demyelinating Diseases; Demyelinations; Diffuse; Essential Amino Acids; Exercise; Experimental Autoimmune Encephalomyelitis; Human; Knowledge; Leucine; Ligand Binding Domain; Ligands; Metabolism; Microglia; Modeling; Motor Activity; Multiple Sclerosis; Muscle; Myelin; Nuclear Hormone Receptors; Nuclear Translocation; Oligodendroglia; Outcome; Pathologic; Performance; Peroxisome Proliferator-Activated Receptors; Physiological; Research; Role; Skeletal Muscle; Testing; base; beta-hydroxyisovaleric acid; brain cell; improved; motor function improvement; multiple sclerosis patient; muscle strength; myelination; novel; remyelination; side effect; stem cells

Pathologically, multiple sclerosis (MS) can be identified by the presence of diffuse, discrete demyelinated areas, called plaques. Demyelination is a major feature of MS and therefore, an approach to the management of MS involves an increase in remyelination of axons, resulting in clinical improvement. Peroxisome proliferator-activated receptor β or δ (PPARβ) being highly expressed in the CNS participates in many brain functions including myelination. Being a nuclear hormone receptor, PPARβ needs ligand(s) for its activation and nuclear translocation. Therefore, identification of new nontoxic ligand of PPARβ would be very important for promoting remyelination. The β-hydroxy β-methylbutyrate (HMB) is available in local GNC stores as a muscle-building supplement in human. It is a physiological molecule that is produced in human through the metabolism of L-leucine. HMB is known to increase exercise-induced gains in muscle size and muscle strength and improve exercise performance. Here, we will test an exciting hypothesis that HMB binds to the ligand-binding domain of PPARβ (Specific aim I) and that HMB and its precursor L-leucine promote maturation of OPCs (Specific aim II) and stimulate remyelination in animal models (cuprizone and experimental autoimmune encephalomyelitis or EAE) of CNS demyelination (Specific aim III) via OPC-specific and/or microglia-specific PPARβ. To investigate whether the muscle building effects of L-leucine and HMB could contribute to improved motor function in cuprizone and EAE models, Specific aim III will also examine the role of skeletal muscle-specific PPARβ. A positive outcome of this cutting-edge R01 proposal will delineate easily available muscle-building supplement HMB as a physiological ligand of PPARβ and enhance the possibility of promoting remyelination and treating patients with MS and other demyelinating disorders with HMB and its precursor L-leucine as primary or adjunct therapy.

在病理学上，多发性硬化症（MS）可以通过弥漫性、离散性脱髓鞘区域（称为斑块）的存在来识别。脱髓鞘是MS的主要特征，因此，MS的管理方法涉及轴突髓鞘再生的增加，从而导致临床改善。过氧化物酶体增殖物激活受体β或δ（Peroxisome proliferator-activated receptor β or δ，PPARβ）在中枢神经系统中高表达，参与包括髓鞘形成在内的多种脑功能。作为一种核激素受体，PPARβ的激活和核转位需要配体的参与。因此，寻找新的无毒的PPARβ配体对促进髓鞘再生具有重要意义。β-羟基β-甲基丁酸酯（HMB）可在当地GNC商店作为人体肌肉建设补充剂获得。它是人体内通过L-亮氨酸代谢产生的一种生理分子。已知HMB可以增加肌肉大小和肌肉力量的运动诱导增益，并改善运动表现。在这里，我们将测试一个令人兴奋的假设，即HMB与PPARβ的配体结合结构域结合（特异性目的I），HMB及其前体L-亮氨酸促进OPC成熟（特异性目的II），并通过OPC特异性和/或小胶质细胞特异性PPARβ刺激CNS脱髓鞘（特异性目的III）的动物模型（铜腙和实验性自身免疫性脑脊髓炎或EAE）的髓鞘再生。为了研究L-亮氨酸和HMB的肌肉构建作用是否有助于改善cuprizone和EAE模型中的运动功能，具体目标III还将研究骨骼肌特异性PPARβ的作用。这项尖端R 01提案的积极结果将描绘容易获得的肌肉建设补充剂HMB作为PPARβ的生理配体，并提高促进髓鞘再生和治疗MS和其他脱髓鞘疾病患者的可能性，HMB及其前体L-亮氨酸作为主要或辅助治疗。