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

项目摘要/摘要 骨骼肌无力是衰老和癌症恶病质的标志，对个体有显著影响 健康跨度和生活质量。尽管有临床意义，但目前还没有药物疗法。 可用于缓解肌肉萎缩和虚弱。这个项目的目标是测试一部小说和 未酰化生长激素释放素有望延缓骨骼肌无力和丢失 在衰老和癌症恶病质中的肌肉质量。Ghrelin是一种荷尔蒙，当 乙酰化Ghrelin(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的急剧上升增加了消瘦条件下的瘦体重，但同时肥胖和 GHSR1a受体敏感性降低会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Ghrelin(UnaG)对肌肉的直接益处，不依赖于GHSR1a 激活。用UnaG孵育成肌细胞可促进分化和融合成肌管，并抑制 糖皮质激素诱导的肌肉萎缩和蛋白水解性标记物。在2天的禁食和14天的去神经期间， 使用基因修饰技术慢性增加循环中的UnaG可防止骨骼肌萎缩 不依赖于生长激素/IGF-1轴通过GHSR1a的激活。这项提案的目标是测试 UnaG在两种不同的退行性疾病中缓解肌肉质量损失和虚弱的能力--石棺减少 癌症恶病质。提出了以下目标：目标1：确定UnaG是否能防止神经源性 通过改变肌肉中蛋白质合成和降解的速度，随着年龄的增长而萎缩。目标2：确定是否 UnaG通过调节钙离子的处理和敏感性来预防随年龄增长的收缩功能障碍。目标 3：确定UnaG是否能预防癌症恶病质的快速消瘦和收缩功能障碍。按顺序 为了了解UnaG对骨骼肌细胞的分子机制，我将学习并执行- ART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 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，临床试验可能是有根据的。UnaG及其合成肽具有极好的安全性 与癌细胞生长无关联的人和动物。 该基金的首席研究员(PI)是范·雷曼博士指导下的博士后研究员 在俄克拉荷马医学研究基金会。PI将学习最先进的分子生物学和综合 他的共同导师本杰明·米勒博士和苏珊·布鲁克斯博士分别提供了生理学技术。这些 在PI的独立实验室中，技术将是至关重要的，并促进他的科学事业。圆周率的原点 导师霍莉·范·雷曼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 在老龄化研究方面取得成功。Van Remman博士将监督项目的整体进展和PI的职业生涯 在指导阶段发展，并确保他安全地过渡到独立。

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.