The role of ghrelin and the ghrelin receptor GHSR1a in sarcopenia of aging

生长素释放肽和生长素释放肽受体 GHSR1a 在衰老性肌肉减少症中的作用

• 批准号: 8182580
• 负责人: Jose M. Garcia
• 金额: $ 7.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8182580
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Activities of Daily Living; Affect; Aged, 80 and over; Aging; Animals; Area; Binding Sites; Chronic Disease; Complication; Consensus; Development; Down-Regulation; Eating; Elderly; Engineering; Fiber; Food; Fracture; Genes; Green Fluorescent Proteins; Health Care Costs; Heart failure; Home environment; Hormones; Hospitalization; In Vitro; Individual; Inflammation; Inflammation Mediators; Insulin-Like Growth Factor I; Intake; Interleukin-6; Knock-out; Longevity; Luciferases; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Muscle; Muscle Cells; Muscle function; Nuclear; Nuclear Magnetic Resonance; Obstructive Lung Diseases; Outcome; Pathway interactions; Patients; Performance; Population; Protein Biosynthesis; Proteins; Proteolysis; Quality of life; Role; Signal Transduction; Staining method; Stains; TNF gene; Testing; Tissues; Transgenic Mice; Weight; Work; design; fall risk; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; improved; mortality; muscle form; novel; prevent; promoter; receptor; research study; sarcopenia

DESCRIPTION (provided by applicant): Sarcopenia, the association of decreased muscle mass and function, is commonly seen in the elderly and it is also a serious complication of many chronic diseases such as cancer, obstructive lung disease and heart failure. This is of significant concern because sarcopenia is associated with poor functionality, impaired ability to perform activities of daily living, loss of independence and increased mortality. There are currently no available treatments for this condition despite the significant burden that sarcopenia represents to the elderly. Several mechanisms are involved in the development of sarcopenia including decreased protein synthesis, increased proteolysis and inflammation through nuclear factor ?B (NF?B)-dependent pathways. Emerging evidence suggests that the hormone ghrelin regulates these and other pathways affecting muscle mass. However, ghrelin's effects on muscle mass and function and the mechanisms mediating its effects in the setting of sarcopenia of aging are not known. The long-term objectives of this application are to establish the mechanisms mediating the action of ghrelin and the ghrelin receptor GHSR1a in sarcopenia of aging. We hypothesize that ghrelin prevents aging-associated sarcopenia by: a) Increasing protein synthesis and decreasing proteolysis, b) downregulating inflammation and NF?B activation, and c) that these effects are at least partially mediated through the ghrelin receptor GHSR1a. Our specific aims are to determine the role of ghrelin and the GHSR1a in regulating muscle mass and function in this setting. Using our model of aging-associated sarcopenia, we will: 1) Establish the extent to which muscle mass, muscle performance, protein synthesis and proteolysis are regulated by ghrelin, 2) Characterize the role of ghrelin in modulating inflammation and NF?B activation during aging, and 3) Determine the role of the ghrelin receptor GHSR1a in this setting. Design and methods: We will characterize the role of ghrelin and the GHSR-1a by establishing our recently developed model of sarcopenia of aging in the background of ghrelin and GHSR-1a wild type and KO animals. Furthermore, we will establish the role of inflammation and NF?B activity by exploiting a 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. In-vitro studies will also be performed to further characterize the mechanisms mediating ghrelin's action. Significance: The present proposal will establish the role of ghrelin and the GHSR1a in the setting of sarcopenia of aging, opening new avenues for its treatment. An improvement in functional performance would allow individuals to stay home longer, decreasing hospitalizations, improving quality of life and reducing healthcare costs. It is possible that improving these outcomes will increase longevity. PUBLIC HEALTH RELEVANCE: The loss of muscle mass and function known as sarcopenia is very common in the elderly, reducing functionality and quality of life, and increasing mortality. The novel hormone ghrelin may prevent the development of sarcopenia and this proposal will determine its effects and mechanisms of action in this setting. The results generated by these studies will help us to develop treatments for sarcopenia; thereby improving quality of life by allowing patients to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare.

描述（由申请人提供）：肌肉减少症，肌肉质量降低和功能的关联，通常在老年人中看到，这也是许多慢性疾病（例如癌症，阻塞性肺部疾病和心力衰竭）的严重并发症。这是一个重大关注的问题，因为肌肉减少症与功能不良，进行日常生活活动，独立性丧失和死亡率增加的能力受损有关。尽管Sarcopenia对老年人造成了重大负担，但目前尚无治疗这种情况。肌肉减少症的发展涉及几种机制，包括蛋白质合成减少，蛋白水解增加和通过核因子的炎症增加？b（nf？b）依赖性途径。新兴的证据表明，激素生长素蛋白调节影响肌肉质量的这些途径和其他途径。然而，尚不清楚生长素素对肌肉质量和功能的影响以及在衰老肌肉减少症中介导其作用的机制。 该应用的长期目标是建立介导生长素蛋白和生长素蛋白受体GHSR1A在衰老的肌肉减少症中的作用的机制。我们假设生长素蛋白可以通过以下方式阻止与衰老相关的肌肉减少症：a）增加蛋白质合成并减少蛋白水解，b）下调炎症和NF？b？b激活，c）这些作用至少通过Ghrelin蛋白受体GHSR1A介导了这些作用。我们的具体目的是确定在这种情况下，在调节肌肉质量和功能中，生长素素和GHSR1A的作用。使用我们的衰老相关肌肉减少症的模型，我们将：1）确定肌肉质量，肌肉性能，蛋白质合成和蛋白水解受到生长素蛋白的调节，2）表征生长素蛋白在调节炎症和Nf？b激活过程中的作用。衰老，3）确定生长素释放蛋白受体GHSR1A在这种情况下的作用。设计和方法：我们将通过在Ghrelin和GHSR-1A野生型和KO动物的背景下建立我们最近开发的肌肉衰老模型来表征Ghrelin和GHSR-1A的作用。此外，我们将通过利用已设计以表达荧光素酶和绿色荧光蛋白的转基因小鼠系来确定炎症和NF？b活性的作用，并控制包含NF？B共有结合位点的启动子。还将进行体外研究，以进一步表征介导Ghrelin作用的机制。意义：目前的提案将确定Ghrelin和GHSR1A在衰老肌肉减少症中的作用，为其治疗开辟新的途径。功能性能的改善将使个人能够待更长的时间，减少住院，改善生活质量并降低医疗保健费用。改善这些结果可能会增加寿命。 公共卫生相关性：肌肉质量和功能称为肌肉减少症在老年人中非常普遍，降低功能和生活质量，并增加死亡率。新型激素生长素释放蛋白可能会阻止肌肉减少症的发展，该建议将决定其在这种情况下的作用和作用机理。这些研究产生的结果将有助于我们开发肌肉减少症的治疗方法。从而通过允许患者停留更长的时间来改善生活质量，从而减少住院需求并降低医疗保健费用。