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: 10545896
• 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/10545896
• 关键词: Actomyosin; Acute; Adult; Affect; Age; Aging; Animals; 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; PRKCA gene; Pathologic; Pathway interactions; Pharmacology; Phase; Phosphorylation; Physiological; Physiology; Postdoctoral Fellow; Principal Investigator; Protein Biosynthesis; 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; base; cancer cachexia; cancer cell; career; career development; clinical candidate; clinically significant; cytokine; effective intervention; energy balance; experience; experimental study; ghrelin; healthspan; improved functioning; in vivo; increased appetite; innovation; lean body mass; middle age; motor neuron function; muscle aging; muscle form; nerve supply; neurogenesis; novel; precursor cell; prevent; protein degradation; receptor; reduced muscle mass; sarcopenia; skeletal muscle wasting; skeletal muscle weakness; skills; 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.

项目概要/摘要 骨骼肌无力是衰老和癌症恶病质的标志，严重影响个体 健康寿命和生活质量。尽管具有临床意义，但目前尚无药物治疗方法 可减轻肌肉萎缩和无力。该项目的目标是测试小说和小说的能力 有前途的药物干预，非酰化生长素释放肽，可延缓骨骼肌无力和丧失 肌肉质量在衰老和癌症恶病质中的作用。胃饥饿素是一种激素，当 酰化生长素释放肽 (AG) 与其在大脑中的受体、生长激素促分泌素受体 1a (GHSR1a) 结合。 AG 的急剧增加会增加消耗状态下的瘦体重，但同时肥胖和肥胖的增加也会增加。 GHSR1a 受体敏感性降低导致萎缩和收缩功能障碍。相比之下，最近的研究 显示非酰化形式的生长素释放肽 (UnAG) 对肌肉有直接有益作用，与 GHSR1a 无关 激活。将成肌细胞与 UnAG 一起孵育可增加肌管的分化和融合，并抑制 糖皮质激素引起的肌肉萎缩和蛋白水解标记物。在 2 天的禁食和 14 天的去神经支配期间， 使用基因改造慢性增加循环UnAG可预防骨骼肌萎缩 与通过 GHSR1a 激活生长激素/IGF-1 轴无关。该提案的目标是测试 UnAG 能够减轻两种不同退行性疾病（肌肉减少症）中肌肉质量损失和肌无力的能力 和癌症恶病质。提出以下目标： 目标 1：确定 UnAG 是否可以预防神经源性 通过改变肌肉中蛋白质合成和降解的速率而随着衰老而萎缩。目标 2：确定是否 UnAG 通过调节钙处理和敏感性来预防随年龄增长而出现的收缩功能障碍。目的 图 3：确定 UnAG 是否可以预防癌症恶病质中的快速消耗和收缩功能障碍。为了 为了了解 UnAG 对骨骼肌细胞的分子机制，我将学习并执行最新技术 艺术分子生物学和综合生理学技术来评估体内蛋白质周转率和钙 肌丝的处理和敏感性（细胞内钙瞬变和摄取）。如果我的结果支持 假设，临床试验可能是有必要的。 UnAG 及其合成肽在以下方面具有出色的安全性： 人类和动物与癌细胞生长没有关联。 该资助项目的首席研究员（PI）是 Van Remmen 博士指导下的博士后研究员 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知识 他的共同导师博士的生理学技术。分别是本杰明·米勒和苏珊·布鲁克斯。这些 技术对于 PI 的独立实验室至关重要，并会促进他的科学事业。 PI 的主要 导师 Holly Van Remmen 博士将培训他氧化还原生物学方面的专业知识，并分享她的经验和 衰老研究取得成功。 Van Remmen 博士将监督项目的整体进展和 PI 的职业生涯 指导阶段的发展并确保他安全过渡到独立。