Muscle building supplement HMB for remyelination

用于髓鞘再生的增肌补充剂 HMB

• 批准号: 10654820
• 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/10654820
• 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; beta-hydroxyisovaleric acid; brain cell; improved; motor function improvement; multiple sclerosis patient; muscle strength; myelination; novel; receptor; remyelination; side effect; stem cells; 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; beta-hydroxyisovaleric acid; brain cell; improved; motor function improvement; multiple sclerosis patient; muscle strength; myelination; novel; receptor; 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.

从病理上讲，多发性硬化症（MS）可以通过存在分散的离散脱髓鞘区域（称为斑块）来识别。脱髓鞘是MS的主要特征，因此，MS管理的一种方法涉及轴突的再髓系增加，从而导致临床改善。在CNS参与包括髓鞘化在内的许多大脑功能中，过氧化物组增殖物激活的受体β或δ（PPARβ）高度表达。 PPARβ作为核骑术受体，需要配体激活和核易位。因此，鉴定新的PPARβ的无毒配体对于促进再生非常重要。 β-羟基β-羟基β-甲基丁酸（HMB）可在局部GNC商店中作为人类的肌肉建设补充剂提供。它是通过L-达氨酸的代谢在人类中产生的物理分子。众所周知，HMB会增加运动引起的肌肉大小和肌肉力量的增长，并提高运动表现。 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和/或小胶质细胞特异性PPARβ。为了研究L-达氨酸和HMB的肌肉构建作用是否可以改善Cuprizone和EAE模型中的运动功能，具体AIM III还将检查骨骼肌特异性PPARβ的作用。这项尖端R01提案的积极结果将描绘出易于获得的肌肉建设补充剂HMB作为PPARβ的物理配体，并增强了促进透明度的可能性，并使用MS和其他脱髓鞘疾病治疗HMB及其前L-服以二甲状腺素作为一级或辅助治疗的患者。