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）： 每年，美国有超过1,500,000个人被诊断出患有癌症。恶病质（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），并且在这些患者中，有多达80％的患者存在厌食症（食物摄入量减少），这导致了在这种情况下的功能性能，生活质量和生存率的下降；但是，缺乏治疗这种情况。 Ghrelin是一种新型的合成马酮，可增加能量摄入量并减少能量消耗和感染，从而增加肌肉和脂肪质量。虽然，其在癌症恶病质中的作用机理尚未完全了解。到目前为止，唯一的识别生长素蛋白的受体是生长的乳腺促分泌受体1a（GHSR-1A），并且该受体不存在于肌肉或脂肪组织中。最近的数据表明，Ghrelin的某些作用是与GHSR-1A无关的。该提案的目的是表征肌肉和脂肪组织中生长素和GHSR-1A激动剂的作用机制，并确定这些机制在癌症cachexia中依赖于GHSR-1A的程度。我们假设生长素蛋白通过诱导的：1）食欲，GH/IGF-I和感染下调的GHSR-1A依赖性增加，以及2）蛋白水解中与GHSR-1A无关的下降，通过直接作用于肌肉细胞。我们还假设生长素蛋白会通过GHSR-1A-依赖性和独立的机制来增加脂质生成并下调肿瘤诱导的卡氏症的脂质氧化和脂解。我们的具体目的是：1）确定生长素蛋白受体GHSR-1A在介导生长素蛋白在啮齿动物肌肉中肿瘤诱导的卡己的作用中的作用。使用我们已经建立的体内模型（Lewis Lung Carcinoma [LLC]诱导的Cachexia）在GHSR-1A WT和KO小鼠中，我们将确定在这种情况下，GHSR-1A激活在调节肌肉质量和强度，炎症，蛋白质分解和蛋白质合成中的作用。 2）表征肌肉中生长素的作用机理GHSR-1A无关。基于我们的初步数据表明，GHSR-1A对于ghrelin不需要防止顺铂诱导的C2C12细胞中的蛋白水解，而生长素蛋白部分预防LLC诱导的GHSR-1A KO中的cachexia，我们将研究我们LLC诱导的Cachexia Model in-Crycry cachexia模型中的这些效果，来自GHSR-1A KO小鼠。我们将表征介导GHSR-1A独立效应的途径，并执行实验以识别负责这些效应的替代接收器。 3）确定GHSR-1A在介导生长素蛋白在脂肪组织中的作用中的作用。如我们的顺铂模型所示，我们将研究生长素蛋白在预防LLC肿瘤诱导的脂肪萎缩以及在这种情况下脂肪生成，脂解和脂质氧化的相对贡献中的作用。使用我们的GHSR-1A WT和KO动物，我们还将确定GHSR-1A在介导Ghrelin在Vivo In-Vivo和Vitro中的作用中的作用。迫切需要开发预防或治疗与癌症有关的脂肪和肌肉浪费的疗法，因为它们大大降低了癌症退伍军人的生活质量。本提案将提供有关生长素素的作用机理的见解，确定这些效应是GHSR-1A依赖性的，哪些是与GHSR-1A无关的，它表征了这两种途径并识别这种新型受体。综上所述，这些实验将确定在这种情况下介导生长素蛋白保护作用的机制，以满足临床需求并填补文献中的空隙。最终，这些结果将允许更好地定位 途径和这种情况的新疗法的发展。其他疾病，例如慢性阻塞性肺部疾病，心力衰竭和老年人的脆弱 随着肌肉和脂肪的流失，将受益于该提案会带来的知识的进步。