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

基本信息

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
项目类别：
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

项目摘要

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，严重影响个体尽管具有临床意义，但非逻辑药物疗法目前仍处于劣势。可用于减轻肌肉萎缩和无力。该项目的目标是测试一种新颖的能力。药物干预，非酰化生长素释放肽，以延缓骨骼肌无力和丧失生长素释放肽是一种在衰老和癌症恶病质中增加食欲的激素。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。相反，最近的研究表明，GHSR1a 受体敏感性降低会导致萎缩和收缩功能障碍。显示非酰化形式的生长素释放肽 (UnAG) 对肌肉具有直接有益作用，与 GHSR1a 无关将成肌细胞与 UnAG 一起孵育会增加肌管的分化和融合，并受到抑制。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）中肌肉质量损失和无力的能力提出以下目标：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来防止衰老引起的萎缩。 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。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（细胞内钙瞬态和吸收）如果我的结果支持这一点。假设，UnAG 及其合成肽在临床试验中具有出色的安全性。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 PI 将在俄克拉荷马州医学研究基金会学习最先进的分子生物学和综合知识。他的共同导师本杰明·米勒（Benjamin Miller）博士和苏珊·布鲁克斯（Susan Brooks）博士分别教授了生理学技术。技术对于 PI 的独立实验室至关重要，并会促进 PI 的主要科学生涯。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 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。