Mechanisms of action of ghrelin in muscle and adipose tissue in cancer cachexia

胃饥饿素在癌症恶病质肌肉和脂肪组织中的作用机制

• 批准号: 9301106
• 负责人: Jose M. Garcia
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301106
• 关键词: Address; Adipose tissue; Affect; Agonist; Animals; Anorexia; Atrophic; Body Weight; Body Weight decreased; Cachexia; Cells; Chronic Obstructive Airway Disease; Cisplatin; Clinical; Clinical Treatment; Clinical Trials; Data; Desire for food; Development; Diagnosis; Disease; Down-Regulation; Eating; Elderly; Energy Intake; Energy Metabolism; Fatty acid glycerol esters; GHS-R1a; Grant; Health Care Costs; Heart failure; Home environment; Hormones; Hospitalization; In Vitro; Individual; Inflammation; Insulin-Like Growth Factor I; Knockout Mice; Knowledge; Lewis Lung Carcinoma; Lipids; Lipolysis; Literature; Malignant Neoplasms; Mediating; Modeling; Mus; Muscle; Muscle Cells; Muscle Weakness; Muscle function; Muscular Atrophy; Pathway interactions; Patients; Performance; Prevalence; Prevention therapy; Protein Biosynthesis; Proteolysis; Quality of life; Receptor Activation; Rodent; Rodent Model; Role; Somatotropin; Testing; Treatment-Related Cancer; Veterans; base; cancer anorexia; cancer cachexia; cancer complication; cancer therapy; clinically relevant; effective therapy; fighting; frailty; ghrelin; ghrelin receptor; improved; in vitro Model; in vivo; in vivo Model; increased appetite; insight; lipid biosynthesis; mortality; muscle form; muscle strength; novel; novel therapeutics; oxidation; prevent; protective effect; public health relevance; receptor; research study; response; skeletal muscle wasting; therapy development; tumor

 DESCRIPTION (provided by applicant): More than 1,500,000 individuals in the US are diagnosed with cancer every year. Cachexia (defined as an involuntary weight loss due to adipose tissue and skeletal muscle loss), and anorexia (decreased food intake) are present in up to 80% of these patients, contributing to the decrease in functional performance, quality of life and survival seen in this setting; however, treatments for this condition are lacking. Ghrelin is a novel anabolic hormone that increases energy intake and decreases energy expenditure and inflammation leading to an increase in muscle and fat mass; although, its mechanisms of action in the setting of cancer cachexia are not fully understood. To this date, the only identify receptor for ghrelin is the growth hormone secretagogue receptor 1a (GHSR-1a) and this receptor is not present in muscle or adipose tissue. Recent data has shown that some of ghrelin's effects are GHSR-1a-independent. The objectives of this proposal are to characterize the mechanisms of action of ghrelin and GHSR-1a agonists in muscle and adipose tissue and to establish the extent to which these mechanisms are GHSR-1a-dependent in cancer cachexia. We hypothesize that ghrelin ameliorates cancer cachexia by inducing: 1) GHSR-1a- dependent increases in appetite, GH/IGF-I and downregulation of inflammation, and 2) GHSR-1a-independent decreases in proteolysis by acting directly on muscle cells. We also hypothesize that ghrelin increases lipogenesis and downregulates lipid oxidation and lipolysis in tumor-induced cachexia through GHSR-1a- dependent and independent mechanisms. Our specific aims are: 1) To determine the role of the ghrelin receptor GHSR-1a in mediating the effects of ghrelin in tumor-induced cachexia in rodent muscle. Using our already established in-vivo model (Lewis Lung Carcinoma [LLC]-induced cachexia) in GHSR-1a WT and KO mice, we will determine the role of GHSR-1a activation in modulating muscle mass and strength, inflammation, proteolysis and protein synthesis in this setting. 2) To characterize GHSR-1a-independent mechanisms of action of ghrelin in muscle. Based on our preliminary data showing that the GHSR-1a is not necessary for ghrelin to prevent cisplatin-induced proteolysis in C2C12 cells, and that ghrelin partially prevent LLC-induced cachexia in GHSR-1a KO, we will study these effects in- vivo in our LLC-induced cachexia model and in-vitro in C2C12 cells and 1ry myocyte culture from GHSR-1a KO mice. We will characterize the pathways mediating these GHSR-1a-independent effects of ghrelin and perform experiments to identify the alternate receptor responsible for these effects. 3) To establish the role of GHSR-1a in mediating the effects of ghrelin in adipose tissue. As shown in our cisplatin model, we will study the role of ghrelin in preventing fat atrophy induced by LLC tumor and the relative contribution of lipogenesis, lipolysis and lipid oxidation in this setting. Using our GHSR-1a WT and KO animals we will also establish the role of GHSR-1a in mediating ghrelin's effect in fat in-vivo and in-vitro. The development of therapies for the prevention or treatment of cancer-related fat and muscle wasting is desperately needed because they significantly reduce quality of life in Veterans with cancer. The present proposal will provide insight into ghrelin's mechanisms of action, determine which of these effects are GHSR- 1a-dependent and which are GHSR-1a-independent, characterize these two pathways and identify this novel receptor. Taken together, these experiments will determine the mechanisms mediating ghrelin's protective effects in this setting, addressing a clinical need and filling a void in the literature. Ultimately, these results will allow for better targeting of this pathway and the development of novel therapies for this condition. Other conditions such as chronic obstructive pulmonary disease, heart failure and frailty of the elderly are also associated with muscle and fat loss and will benefit from the advance in knowledge that this proposal will bring.

 描述（由申请人提供）： 美国每年有超过 1,500,000 人被诊断患有癌症（定义为由于脂肪组织和骨骼肌损失而导致的非自愿体重减轻），其中高达 80% 的患者患有厌食症（食物摄入量减少）。导致这种情况下的功能表现、生活质量和生存率下降；然而，缺乏针对这种情况的治疗方法，饥饿素是一种增加能量的新型合成代谢激素。摄入量并减少能量消耗和炎症，导致肌肉和脂肪量增加；尽管迄今为止，其在癌症恶病质中的作用机制尚未完全了解，生长激素释放肽的唯一识别受体是生长激素促分泌素受体。 1a (GHSR-1a) 且该受体不存在于肌肉或脂肪组织中。最近的数据表明，某些 ghrelin 的作用与 GHSR-1a 无关。本提案的目的是表征其机制。 ghrelin 和 GHSR-1a 激动剂在肌肉和脂肪组织中的作用，并确定这些机制在癌症恶病质中 GHSR-1a 依赖性的程度。我们研究 ghrelin 通过诱导以下作用改善癌症恶病质：1) GHSR-1a 依赖性增加。食欲、GH/IGF-I 和炎症下调，以及 2) GHSR-1a 不依赖的直接作用减少蛋白水解作用我们还发现，生长素释放肽通过 GHSR-1a 依赖性和独立机制增加脂肪生成并下调肿瘤诱导的恶病质中的脂质氧化和脂肪分解。使用我们已经建立的体内模型（刘易斯肺癌）介导胃饥饿素对啮齿动物肌肉肿瘤引起的恶病质的影响。 [LLC] 诱导的恶病质）在 GHSR-1a WT 和 KO 小鼠中，我们将确定 GHSR-1a 激活在这种情况下调节肌肉质量和强度、炎症、蛋白水解和蛋白质合成中的作用 2) 表征 GHSR-1a。 - ghrelin 在肌肉中的独立作用机制基于我们的初步数据，表明 GHSR-1a 对于 ghrelin 预防顺铂诱导的蛋白水解不是必需的。 C2C12 细胞，并且 ghrelin 部分预防 GHSR-1a KO 中 LLC 诱导的恶病质，我们将在 LLC 诱导的恶病质模型中体内研究这些效应，并在来自 GHSR-1a KO 小鼠的 C2C12 细胞和 1ry 肌细胞培养物中研究这些效应我们将描述介导 ghrelin 的这些 GHSR-1a 独立作用的途径，并进行实验以确定负责这些作用的替代受体 3)。确定 GHSR-1a 在介导 ghrelin 在脂肪组织中的作用 如我们的顺铂模型所示，我们将研究 ghrelin 在预防 LLC 肿瘤诱导的脂肪萎缩中的作用以及脂肪生成、脂肪分解和脂质氧化的相对贡献。在这种情况下，使用我们的 GHSR-1a WT 和 KO 动物，我们还将确定 GHSR-1a 在介导 ghrelin 对脂肪的作用中的作用。迫切需要开发用于预防或治疗与癌症相关的脂肪和肌肉消耗的疗法，因为它们会显着降低患有癌症的退伍军人的生活质量。作用，确定这些效应中哪些是 GHSR-1a 依赖性的，哪些是 GHSR-1a 独立的，表征这两种途径并识别这种新受体。总之，这些实验将确定介导 ghrelin 保护性的机制。在此背景下的效果，解决临床需求并填补文献空白，最终，这些结果将有助于更好地针对这一点。 慢性阻塞性肺病、心力衰竭和老年人虚弱等其他疾病也与此相关。 随着肌肉和脂肪的减少，并将受益于该提案带来的知识进步。