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: 8311634
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311634
• 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.

描述（申请人提供）：肌少症是一种肌肉质量和功能下降的症状，常见于老年人，也是癌症、阻塞性肺病和心力衰竭等许多慢性疾病的严重并发症。这是一个值得关注的问题，因为肌肉减少症与功能差、日常生活活动能力受损、独立性丧失和死亡率增加有关。尽管肌肉减少症给老年人带来了巨大的负担，但目前还没有针对这种情况的治疗方法。肌肉减少症的发生涉及多种机制，包括蛋白质合成减少、蛋白水解增加以及核因子 B (NF?B) 依赖性途径引起的炎症。新的证据表明，生长素释放肽激素调节这些和其他影响肌肉质量的途径。然而，生长素释放肽对肌肉质量和功能的影响以及在衰老性肌肉减少症的情况下介导其影响的机制尚不清楚。 本申请的长期目标是建立介导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的机制。我们假设 ghrelin 通过以下方式预防与衰老相关的肌肉减少症：a) 增加蛋白质合成和减少蛋白水解，b) 下调炎症和 NF?B 激活，c) 这些作用至少部分是通过 ghrelin 受体 GHSR1a 介导的。我们的具体目标是确定 ghrelin 和 GHSR1a 在这种情况下调节肌肉质量和功能的作用。利用我们的衰老相关肌肉减少症模型，我们将：1) 确定 ghrelin 调节肌肉质量、肌肉性能、蛋白质合成和蛋白水解的程度，2) 表征 ghrelin 在调节衰老过程中炎症和 NF?B 激活中的作用，以及 3) 确定 ghrelin 受体 GHSR1a 在此环境中的作用。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衰老肌肉减少症模型来表征 ghrelin 和 GHSR-1a 的作用。此外，我们将通过利用转基因小鼠品系来确定炎症和 NFκB 活性的作用，该转基因小鼠品系已被设计为在包含 NFκB 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。还将进行体外研究，以进一步表征介导生长素释放肽作用的机制。意义：本提案将确定 ghrelin 和 GHSR1a 在衰老性肌肉减少症中的作用，为其治疗开辟新途径。功能表现的改善将使个人能够在家里呆更长时间，减少住院次数，提高生活质量并降低医疗费用。改善这些结果可能会延长寿命。