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

描述(申请人提供)：骨质疏松症，肌肉质量和功能下降的联系，常见于老年人，也是许多慢性疾病的严重并发症，如癌症、阻塞性肺病和心力衰竭。这是非常令人担忧的，因为石棺减少与功能低下、日常生活活动能力受损、丧失独立性和死亡率增加有关。尽管石棺减少给老年人带来了巨大的负担，但目前还没有可用的治疗方法。一些机制参与了骨质疏松症的发展，包括蛋白质合成减少，蛋白分解增加，以及通过核因子B(NF？B)依赖的途径引起炎症。新出现的证据表明，生长激素Ghrelin调节这些和其他影响肌肉质量的途径。然而，Ghrelin对肌肉质量和功能的影响以及其在老年性骨质疏松症中的作用机制尚不清楚。该应用的长期目标是建立Ghrelin和Ghrelin受体GHSR1a在老年性骨质疏松症中的作用机制。我们假设Ghrelin通过增加蛋白质合成和减少蛋白质分解，b)下调炎症和核因子B的激活，以及c)这些作用至少部分地通过Ghrelin受体GHSR1a来调节，从而预防与衰老相关的骨质疏松症。我们的具体目标是确定在这种情况下Ghrelin和GHSR1a在调节肌肉质量和功能方面的作用。使用我们的衰老相关性骨质疏松症模型，我们将：1)确定Ghrelin对肌肉质量、肌肉性能、蛋白质合成和蛋白分解的调节程度，2)表征Ghrelin在调节衰老过程中的炎症和核因子？B激活中的作用，以及3)确定Ghrelin受体GHSR1a在这一环境中的作用。设计和方法：我们将通过建立我们最近开发的以Ghrelin和GHSR-1a野生型和KO动物为背景的衰老石棺减少模型来表征Ghrelin和GHSR-1a的作用。此外，我们将通过利用一个转基因小鼠系来确定炎症和核因子？B活性的作用，该转基因鼠系已经被设计成在含有核因子？B共同结合位点的启动子的控制下表达荧光素酶和绿色荧光蛋白。体外研究也将被进行，以进一步表征介导Ghrelin作用的机制。意义：本提案将确定Ghrelin和GHSR1a在老年性骨质疏松症中的作用，为其治疗开辟新的途径。功能表现的改善将使个人在家中呆得更长时间，减少住院，提高生活质量，并降低医疗成本。改善这些结果可能会延长寿命。

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.