Muscle building supplement HMB for remyelination

用于髓鞘再生的增肌补充剂 HMB

• 批准号: 10281373
• 负责人: KALIPADA PAHAN
• 金额: $ 6.54万
• 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/10281373
• 关键词: Administrative Supplement; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amino Acids; Animal Model; Area; Autopsy; Axon; Binding; Brain; Cells; Clinical; Cuprizone; Demyelinating Diseases; Demyelinations; Diffuse; Essential Amino Acids; Exercise; Experimental Autoimmune Encephalomyelitis; Genes; Grant; Hippocampus (Brain); Human; Impaired cognition; Investigation; Leucine; Ligand Binding Domain; Ligands; Metabolism; Modeling; Motor Activity; Multiple Sclerosis; Mus; Muscle; Myelin; Neurodegenerative Disorders; Nuclear Hormone Receptors; Nuclear Translocation; Oligodendroglia; Oral Administration; Outcome; Pathologic; Performance; Peroxisome Proliferator-Activated Receptors; Physiological; Research; Skeletal Muscle; Testing; United States National Institutes of Health; base; beta-hydroxyisovaleric acid; brain cell; cognitive function; effective therapy; improved; interest; mind control; mouse model; multiple sclerosis patient; muscle strength; myelination; novel; remyelination; response; side effect; stem cells; therapeutic target

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. Our preliminary results show that HMB may bind and activate PPARβ and stimulate the maturation of oligodendroglial progenitor cells (OPCs) to oligodendrocytes (OL), myelin-producing cells in the CNS. Therefore, here, we will test an exciting hypothesis that HMB binds to the ligand- binding domain of PPARβ and that HMB and its precursor L-leucine promote maturation of OPCs and stimulate remyelination in animal models (cuprizone and experimental allergic encephalomyelitis) of CNS demyelination via PPARβ. Administrative supplement: Alzheimer’s disease (AD) is the most common neurodegenerative disorder in humans and despite intense investigations, no effective therapy is available to halt the progression of AD. Interestingly, our preliminary results show marked demyelination in the hippocampus and cortex of postmortem AD brains as compared to age-matched control brains with no cognitive impairment. Similarly, we have seen demyelination in the hippocampus and cortex of 5XFAD mice, but not age-matched non-transgenic mice. Since the muscle building supplement HMB activates PPARβ, increases myelin-specific genes and stimulates the maturation of OPC to OL, here, in response to NOT-AG-20-034 entitled “Notice of Special Interest: Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease”, we have planned to test an exciting hypothesis that oral administration of HMB and its precursor Leu stimulates remyelination and improves cognitive functions in 5XFAD mouse model of AD via PPARβ. A positive outcome of this administrative supplement will indicate whether demyelination/remyelination is a therapeutic target in AD, enhance the possibility of promoting remyelination and improving cognitive functions in AD patients with muscle-building supplement HMB and a simple non-toxic amino acid L-leucine as primary or adjunct therapy.

在病理学上，多发性硬化症（MS）可以通过存在弥漫性、离散性和不稳定性来识别。 脱髓鞘区域，称为斑块。脱髓鞘是MS的主要特征，因此， 治疗MS的方法包括增加轴突的髓鞘再生，导致 临床改善。过氧化物酶体增殖物激活受体β或δ（过氧化物酶体增殖物激活受体β或δ）高度 在CNS中表达的β-淀粉样蛋白参与许多脑功能，包括髓鞘形成。作为一个 作为核激素受体，PPARβ的激活和核转位需要配体。 因此，新的无毒配体的鉴定对于PPARβ的研究具有重要意义。 促进髓鞘再生β-羟基β-甲基丁酸酯（HMB）可在当地GNC获得 在人体内储存作为肌肉增强补充剂。它是一种生理分子， 在人体内通过L-亮氨酸的代谢。已知HMB会增加运动诱导的 增加肌肉大小和肌肉力量，提高运动表现。我们的初步 结果表明，HMB可以结合并激活PPARβ，刺激细胞成熟， 少突胶质祖细胞（OPCs）向少突胶质细胞（OL）转化， CNS。因此，在这里，我们将测试一个令人兴奋的假设，即HMB结合配体- HMB和它的前体L-亮氨酸促进了 OPCs和刺激髓鞘再生的动物模型（cuprizone和实验过敏性 脑脊髓炎）的CNS脱髓鞘通过PPARβ。 管理补充：阿尔茨海默病（AD）是最常见的神经退行性疾病， 尽管进行了大量的研究，但没有有效的治疗方法可以阻止人类的疾病， AD的进展。有趣的是，我们的初步结果显示， 与年龄匹配的对照脑相比， 没有认知障碍同样，我们在海马体中也看到了脱髓鞘， 5XFAD小鼠的皮质，但不是年龄匹配的非转基因小鼠。自从肌肉锻炼 补充HMB激活PPARβ，增加髓鞘特异性基因，并刺激 OPC到OL的成熟，在这里，响应NOT-AG-20-034题为“特别通知 兴趣：以阿尔茨海默氏症为重点的NIH赠款的行政补充， 阿尔茨海默氏病”，我们计划测试一个令人兴奋的假设，口服给药 HMB及其前体Leu刺激髓鞘再生并改善认知功能， 5XFAD小鼠模型通过PPARβ。这一行政补充的积极成果 将表明脱髓鞘/髓鞘再生是否是AD的治疗靶点，增强脱髓鞘/髓鞘再生的作用。 促进髓鞘再生和改善AD患者认知功能的可能性 肌肉建设补充HMB和一个简单的无毒氨基酸L-亮氨酸作为主要或 辅助治疗