Mechanisms of action of ghrelin in muscle and adipose tissue in cancer-related ca

生长素释放肽在癌症相关癌症肌肉和脂肪组织中的作用机制

• 批准号: 7908888
• 负责人: Jose M. Garcia
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908888
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Address; Adipose tissue; Affect; Aging; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Binding Sites; Biological Preservation; Body Composition; Body Weight; Body Weight decreased; Boxing; Cachexia; Carnitine; Cell Line; Chronic; Chronic Obstructive Airway Disease; Cisplatin; Clinical; Complication; Consensus; Data; Deposition; Diagnosis; Disease; Down-Regulation; Eating; Energy Intake; Energy Metabolism; Engineering; Environment; Enzymes; Fatty acid glycerol esters; Fatty-acid synthase; Genes; Goals; Grant; Green Fluorescent Proteins; Health Care Costs; Heart Diseases; Heart failure; Home environment; Hormones; Hospitalization; IGF1 gene; Indirect Calorimetry; Individual; Inflammation; Inflammation Mediators; Inflammatory; Insulin-Like Growth Factor I; Interleukin-1 beta; Interleukin-6; Kidney Failure; Knock-out; Knockout Mice; Knowledge; Lewis Lung Carcinoma; Lipids; Lipolysis; Literature; Luciferases; Lung; Lung diseases; Malignant Epithelial Cell; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator of activation protein; Medical center; Medicine; Modeling; Muscle; Muscle Proteins; Muscle function; Muscular Atrophy; NF-kappa B; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrology; Nuclear Magnetic Resonance; Obesity; Pathway interactions; Patients; Performance; Physicians; Prevalence; Proteolysis; Proto-Oncogene Proteins c-akt; Publications; Quality of life; Relative (related person); Research; Research Design; Research Methodology; Rodent Model; Role; Scientist; Sodium Salicylate; Stomach; Testing; Tissues; Transferase; Transgenic Animals; Transgenic Mice; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; United States National Institutes of Health; Veterans; abstracting; base; cancer therapy; chemotherapy; college; desaturase; effective therapy; feeding; ghrelin; ghrelin receptor; human GHR protein; improved; increased appetite; inhibitor/antagonist; innovation; interest; lipid biosynthesis; member; mortality; multicatalytic endopeptidase complex; muscle form; novel; outcome forecast; oxidation; pegvisomant; perilipin; prevent; programs; promoter; protective effect; protein metabolism; public health relevance; research study; response; stearoyl-coenzyme A; sterol esterase; therapy development; tumor; ubiquitin ligase; wasting

DESCRIPTION (provided by applicant): 6. Project Summary/Abstract Every year, over 1.5 million individuals in the US are diagnosed with cancer. Cachexia, defined as an involuntary weight loss >5%, is present in up to 80% of these patients and it encompasses the loss of muscle and fat mass. Cachexia also contributes to a decrease in functional performance, quality of life and survival. However, treatments for this condition are lacking. Ghrelin, a novel hormone released primarily by the stomach stimulates GH secretion, increases energy intake and decreases energy expenditure. More recently it has been postulated to have anti-inflammatory actions. In our model of cachexia, administration of ghrelin induced an increase in lean body mass (LBM) and fat mass. However, its mechanisms of action in this setting are not fully understood. The long-term objective of this research is to determine the extent to which ghrelin improves cachexia and to establish the mechanisms mediating ghrelin's action in muscle and adipose tissue in this setting. Our hypotheses are that in the setting of cancer- and cisplatin-induced cachexia, ghrelin will prevent muscle wasting by downregulating proteolysis through the ubiquitin-proteasome pathway. These changes will be mediated through: a) increases in energy intake, b) activation of insulin-like growth factor-1 (IGF-1)-dependent pathways and c) downregulation of nuclear factor kappa B (NF:B)-dependent inflammatory pathways. We also hypothesize that ghrelin will prevent fat loss by decreasing lipolysis and by favoring fat storage. These changes will be mediated through: a) increasing food intake, b) decreasing energy expenditure and c) downregulating NF:B-dependent inflammatory pathways. The specific aims are to: 1) Establish the mechanisms mediating ghrelin-induced muscle preservation in the setting of cisplatin-induced cachexia; 2) Determine the mechanisms involved in ghrelin-induced fat deposition in the setting of cisplatin-induced cachexia; and 3) Characterize the effects of ghrelin in a tumor model of cachexia induced by the Lewis lung carcinoma (LLC) cell line. Research Design and Methods: In our rodent model of cisplatin-induced cachexia we have observed that ghrelin prevents cisplatin-induced fat and muscle atrophy. We are now proposing to determine the mechanisms involved in this setting and further characterize these pathways by using a different model of cachexia induced by LLC cell line. We will determine the role of endogenous ghrelin and the ghrelin receptor GHSR-1a by setting up our model of cachexia in ghrelin and GHSR1a knock-outs. We will establish the role of NF:B and inflammation by exploiting a new transgenic mouse line that has been engineered to express luciferase and green fluorescent protein under control of a promoter that contains NF:B consensus binding sites. The role of NF:B will be confirmed by using NF:B antagonists. The extent to which food intake regulates the pathways controlling fat and muscle mass will be established by performing pair-feeding experiments. The relative contribution of GH/IGF-1 activation to ghrelin's action will be tested by the administration of IGF-1 and GH receptor antagonists. Energy expenditure measurements will be performed by indirect calorimetry. Based on the data generated in our current model, we also will test the hypothesis that the same mechanisms are implicated in the setting of LLC tumor -induced cachexia. Taken together, these experiments will determine the mechanisms mediating ghrelin's protective effects in the setting of fat and muscle wasting related to cancer, addressing a clinical need and filling a void in the literature. PUBLIC HEALTH RELEVANCE: 7. PROJECT NARRATIVE Cancer will affect 1 in 2 veterans and involuntary weight loss (also known as cachexia) resulting from a loss of fat and muscle mass will affect the vast majority of these patients. Cachexia often reduces functionality leading to a decrease in quality of life, poor response to anti-cancer therapies and increased mortality. Currently there is no effective way to treat cachexia. The novel hormone ghrelin increases appetite and body weight. This proposal will determine its effects and mechanisms of action in muscle and fat in the setting of cachexia. The results generated by this proposal will help us to develop treatments for cachexia, improving quality of life. By increasing muscle mass and function, patients will tolerate more effective treatments. They also will be able to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare. Cachexia is also a complication of many other conditions including lung and heart disease and aging, the knowledge generated through this proposal also will help us in establishing new therapies for these conditions.

描述（由申请人提供）： 6. 项目摘要/摘要 美国每年有超过 150 万人被诊断患有癌症。恶病质被定义为非自愿体重减轻>5%，在这些患者中高达 80% 存在，包括肌肉和脂肪量的减少。恶病质还会导致功能表现、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。胃饥饿素是一种主要由胃释放的新型激素，可刺激 GH 分泌，增加能量摄入并减少能量消耗。最近，人们推测它具有抗炎作用。在我们的恶病质模型中，施用生长素释放肽会导致去脂体重（LBM）和脂肪量增加。然而，其在这种情况下的作用机制尚未完全了解。这项研究的长期目标是确定生长素释放肽改善恶病质的程度，并建立介导生长素释放肽在这种情况下在肌肉和脂肪组织中发挥作用的机制。我们的假设是，在癌症和顺铂引起的恶病质的情况下，生长素释放肽将通过泛素-蛋白酶体途径下调蛋白水解作用，从而防止肌肉萎缩。这些变化将通过以下方式介导：a) 能量摄入增加，b) 胰岛素样生长因子-1 (IGF-1) 依赖性途径的激活，以及 c) 核因子 kappa B (NF:B) 依赖性炎症的下调途径。我们还假设生长素释放肽将通过减少脂肪分解和促进脂肪储存来防止脂肪减少。这些变化将通过以下方式介导：a) 增加食物摄入量，b) 减少能量消耗和 c) 下调 NF:B 依赖性炎症途径。具体目标是： 1）建立在顺铂引起的恶病质情况下介导生长素释放肽诱导的肌肉保存的机制； 2) 确定在顺铂引起的恶病质情况下胃饥饿素诱导的脂肪沉积的机制； 3) 表征生长素释放肽在 Lewis 肺癌 (LLC) 细胞系诱导的恶病质肿瘤模型中的作用。研究设计和方法：在我们的顺铂引起的恶病质的啮齿动物模型中，我们观察到生长素释放肽可以防止顺铂引起的脂肪和肌肉萎缩。我们现在提议确定这种情况所涉及的机制，并通过使用 LLC 细胞系诱导的不同恶病质模型进一步表征这些途径。我们将通过在 ghrelin 和 GHSR1a 敲除中建立恶病质模型来确定内源性 ghrelin 和 ghrelin 受体 GHSR-1a 的作用。我们将通过开发一种新的转基因小鼠系来确定 NF:B 和炎症的作用，该小鼠系经过工程改造，在包含 NF:B 共有结合位点的启动子控制下表达荧光素酶和绿色荧光蛋白。 NF:B 的作用将通过使用 NF:B 拮抗剂来证实。食物摄入对脂肪和肌肉质量控制途径的调节程度将通过配对喂养实验来确定。 GH/IGF-1 激活对生长素释放肽作用的相对贡献将通过施用 IGF-1 和 GH 受体拮抗剂来测试。能量消耗测量将通过间接量热法进行。根据我们当前模型中生成的数据，我们还将检验以下假设：LLC 肿瘤诱发的恶病质涉及相同的机制。总而言之，这些实验将确定介导生长素释放肽在与癌症相关的脂肪和肌肉消耗情况下的保护作用的机制，满足临床需求并填补文献空白。 公共卫生相关性： 7. 项目叙述 癌症将影响二分之一的退伍军人，而由于脂肪和肌肉质量减少而导致的非自愿体重减轻（也称为恶病质）将影响绝大多数这些患者。恶病质通常会降低功能，导致生活质量下降、抗癌治疗反应不佳以及死亡率增加。目前尚无治疗恶病质的有效方法。新型激素胃饥饿素可以增加食欲和体重。该提案将确定其在恶病质情况下对肌肉和脂肪的影响和作用机制。该提案产生的结果将帮助我们开发恶病质的治疗方法，提高生活质量。通过增加肌肉质量和功能，患者将能够耐受更有效的治疗。他们还可以在家里待更长时间，从而减少住院需求并降低医疗费用。恶病质也是许多其他疾病的并发症，包括肺病、心脏病和衰老，通过该提案产生的知识也将帮助我们为这些疾病建立新的疗法。