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.

项目总结/摘要 骨骼肌无力是衰老和癌症恶病质的标志， 健康寿命和生活质量。尽管具有临床意义，但目前还没有药物治疗。 可用于缓解肌肉萎缩和虚弱。这个项目的目标是测试一个小说的能力， 有前途的药理学干预，非酰化生长激素释放肽，以延迟骨骼肌无力和损失 和癌症恶病质中的肌肉质量。胃饥饿素是一种激素，当胃饥饿时会增加食欲。 酰化生长素释放肽（AG）与其在脑中的受体生长激素促分泌素受体-1a（GHSR 1a）结合。 AG的急剧上升增加了消瘦状态下的瘦体重，但同时增加了肥胖和 GHSR 1a受体敏感性降低导致萎缩和收缩功能障碍。相反，最近的研究 显示出非酰化形式的生长激素释放肽（UnAG）对肌肉的直接有益作用，不依赖于GHSR 1a activation.用UnAG孵育成肌细胞增加分化和融合成肌管，并抑制成肌细胞的分化和融合。 糖皮质激素诱导的肌肉萎缩和蛋白水解标记物。在2天禁食和14天去神经期间， 使用遗传修饰的循环UnAG的慢性增加防止了骨骼肌萎缩 独立于生长激素/IGF-1轴通过GHSR 1a的激活。本提案的目的是测试 在两种不同的退行性疾病-肌肉减少症中，UnAG减轻肌肉质量损失和无力的能力 和癌症恶病质。目的1：确定UnAG是否能预防神经原性 通过改变肌肉中蛋白质合成和降解的速率而随衰老而萎缩。目标2：确定是否 UnAG通过调节钙处理和敏感性来防止收缩功能障碍。目的 3：确定UnAG是否可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，我将学习和执行国家的- 采用分子生物学和综合生理学技术评估体内蛋白质周转率和钙离子浓度 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，临床试验可能是必要的。UnAG及其合成肽具有优异的安全性， 与癌细胞生长无关联的人类和动物。 该基金的主要研究者（PI）是货车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 分别从他的共同导师本杰明米勒和苏珊布鲁克斯博士那里学习生理学技术。这些 技术将在PI的独立实验室中发挥关键作用，并促进他的科学事业。PI的主要 导师，冬青博士货车雷门，将培训他在氧化还原生物学的专业知识，并分享她的经验， 老龄化研究的成功。货车Remmen博士将监督项目的总体进展和PI的职业生涯 在辅导阶段的发展，并确保他向独立的安全过渡。