The role of unacylated ghrelin on age-associated progressive muscle weakness and cachexia elicited by cancer

非酰化生长素释放肽对年龄相关的进行性肌肉无力和癌症引起的恶病质的作用

• 批准号: 10609936
• 负责人: Bumsoo Ahn
• 金额: $ 24.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609936
• 关键词: Actomyosin; Acute; Acylation; Adult; Affect; Age; Aging; Animals; Applied Skills; Atrophic; Binding; Biological Assay; Biology; Brain; C26 tumor; Cachexia; Calcium; Cancer Cell Growth; Cancer Model; Cells; Chronic; Clinical Trials; Coculture Techniques; Colon Carcinoma; Colorectal Cancer; Cyclic AMP-Dependent Protein Kinases; Data; Degenerative Disorder; Denervation; Ensure; FRAP1 gene; Fasting; Fiber; Foundations; Functional disorder; GHS-R1a; Generations; Genetic; Glucocorticoids; Goals; Grant; Holly; Hormones; Human; Impairment; Incubated; Individual; Inflammation; Inflammatory; Insulin-Like Growth Factor I; Interferon Type II; Intervention; Laboratories; Lead; Learning; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Medical Research; Mentors; Mentorship; Microfilaments; Mitochondria; Modeling; Modification; Molecular; Molecular Biology; Monitor; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Myoblasts; Myopathy; Nerve; Nerve Degeneration; Neurons; Obesity; Oklahoma; Oxidation-Reduction; Oxidative Stress Induction; PRKCA gene; Pathologic; Pathway interactions; Permeability; Phase; Phosphorylation; Physiological; Physiology; Postdoctoral Fellow; Principal Investigator; Proliferating; Protein Biosynthesis; Protein Degradation Inhibition; Protein Kinase; Proteins; Quality of life; Research; Role; Safety; Secure; Signal Transduction; Skeletal Muscle; Somatotropin; TNF gene; Techniques; Testing; Thinness; Training; Translations; Wasting Syndrome; Wild Type Mouse; cancer cachexia; cancer cell; career; career development; clinical candidate; clinically significant; cytokine; effective intervention; energy balance; experience; experimental study; ghrelin; healthspan; improved; in vivo; increased appetite; innovation; lean body mass; middle age; motor neuron function; muscle aging; muscle form; nerve supply; neurogenesis; novel; pharmacologic; precursor cell; prevent; protein degradation; receptor; reduced muscle mass; sarcopenia; skeletal muscle wasting; skeletal muscle weakness; success; synthetic peptide; systemic inflammatory response; uptake; wasting

Project Summary/Abstract Skeletal muscle weakness is a hallmark of aging and cancer cachexia that significantly affect individual healthspans and quality of life. Despite the clinical significance, no pharmacological therapies are currently available to mitigate muscle atrophy and weakness. The goal of this project is to test the ability of a novel and promising pharmacological intervention, unacylated ghrelin, to delay skeletal muscle weakness and loss of muscle mass in aging and in cancer cachexia. Ghrelin is a hormone that increases appetite when the acylated ghrelin (AG) binds to its receptor in the brain, growth hormone secretagogue receptor-1a (GHSR1a). An acute rise in AG increases lean mass in wasting conditions, but a concurrent increase in adiposity and decreased sensitivity in GHSR1a receptor lead to atrophy and contractile dysfunction. In contrast, recent studies show a direct beneficial effect of the unacylated form of ghrelin (UnAG) on muscle, independent of GHSR1a activation. Incubating myoblast with UnAG increases differentiation and fusion into myotubes, and inhibited glucocorticoid-induced muscle atrophy and proteolytic markers. During a 2-day fasting and 14-day denervation, a chronic increase in circulating UnAG using a genetic modification prevented skeletal muscle atrophy independent of activation of the growth hormone/IGF-1 axis via GHSR1a. The goal of this proposal is to test the ability of UnAG to mitigate loss of muscle mass and weakness in two distinct degenerative conditions-sarcopenia and cancer cachexia. The following aims are proposed: Aim 1: To determine whether UnAG prevents neurogenic atrophy with aging by altering rates of protein synthesis and degradation in muscle. Aim 2: To determine whether UnAG prevents contractile dysfunction with aging through modulations of calcium handling and sensitivity. Aim 3: To determine whether UnAG prevents a rapid wasting and contractile dysfunction in cancer cachexia. In order to understand the molecular mechanisms of UnAG on skeletal muscle cells, I will learn and perform state-of-the- art molecular biology and integrative physiology techniques to assess in vivo protein turnover rate and calcium handling and sensitivity of myofilaments (intracellular calcium transient and uptake). If my results support the hypothesis, clinical trials may be warranted. UnAG and its synthetic peptides have excellent safety profiles in humans and animals with null association to cancer cell growth. The principal investigator (PI) of this grant is a postdoctoral fellow under the mentorship of Dr. Van Remmen at Oklahoma Medical Research Foundation. The PI will learn state-of-the-art molecular biology and integrative physiology techniques from his co-mentors Drs. Benjamin Miller and Susan Brooks, respectively. These techniques will be critical in the PI’s independent laboratory and boost his scientific career. The PI’s primary mentor, Dr. Holly Van Remmen, will train him the expertise in redox biology and share her experience and success in aging research. Dr. Van Remmen will monitor overall progress of the project and the PI’s career development during the mentored phase and ensure his secure transition toward independence.

项目摘要/摘要 骨骼肌无力是衰老和癌症恶病质的标志，严重影响了个体 健康范围和生活质量。尽管具有临床意义，但目前尚无药理疗法 可用于减轻肌肉萎缩和无力。该项目的目的是测试小说的能力和 有希望的药物干预措施，未酰化的生长素素，延迟骨骼肌肉无力和损失 衰老和癌症恶病质中的肌肉质量。 Ghrelin是一匹马，可以增加食欲 酰化的生长素蛋白（Ag）与其在大脑中的受体结合，生长的Horsene secretagogue受体-1A（GHSR1A）。 Ag急性增加会增加浪费条件下的瘦质量，但同时增加肥胖和增加 GHSR1A受体的敏感性降低导致萎缩和收缩功能障碍。相反，最近的研究 在肌肉中表现出非囊化形式的生长素（unag）的直接有益作用，与GHSR1A无关 激活。与Unag一起孵育肌细胞会增加分化和融合到肌管中，并抑制 糖皮质激素引起的肌肉萎缩和蛋白水解标记。在2天的禁食和14天的改造中， 使用遗传修饰预防骨骼肌萎缩的慢性增加循环统一 独立于通过GHSR1A激活生长马/IGF-1轴。该提议的目的是测试 在两个不同的退化性疾病中，脱离肌肉质量和无力的能力 - 肌肉减少症 和癌症恶病质。提出了以下目的：目标1：确定Unag是否阻止神经源性 通过改变蛋白质合成速率和肌肉降解的衰老，萎缩。目标2：确定是否 通过钙处理和敏感性调节，Unag可防止收缩功能障碍，并通过衰老而衰老。目的 3：确定Unag是否可以防止癌症恶病质中的快速浪费和收缩功能障碍。为了 为了了解骨骼肌细胞上Unag的分子机制，我将学习并执行最新的 ART分子生物学和综合生理技术评估体内蛋白质周转率和钙 肌膜的处理和灵敏度（细胞内钙瞬态和摄取）。如果我的结果支持 假设，可能需要进行临床试验。 Unag及其合成Pepperides具有出色的安全性。 人类和动物与癌细胞生长无效的动物。 该赠款的首席研究员（PI）是范·雷曼（Van Remmen）博士的心态下的博士后研究员 在俄克拉荷马州医学研究基金会。 PI将学习最先进的分子生物学和综合性 他的联合主管Drs的生理技术。本杰明·米勒（Benjamin Miller）和苏珊·布鲁克斯（Susan Brooks）。这些 技术在PI的独立实验室中至关重要，并提高他的科学生涯。 PI的主要 导师霍莉·范·雷曼（Holly Van Remmen）博士将培训他在氧化还原生物学方面的专业知识，并分享她的经验和 衰老研究的成功。 Van Remmen博士将监控该项目的整体进展和PI的职业 在修补阶段的发展，并确保他向独立的安全过渡。