The regulation of protein translation in skeletal muscle by androgens

描述（由申请人提供）：我正在追求这个职业发展奖，以培养一个转化研究的职业生涯，专注于阐明机制和发展策略，以减轻骨骼肌萎缩。与年龄和疾病相关的肌肉质量损失与巨大的社会和经济成本相关，并表现为力量受损、功能受限、身体残疾和丧失独立性。遗憾的是，对抗肌肉萎缩的治疗方法很少，现有的治疗方法发挥作用的方法仍然知之甚少。这一职业发展奖项的主要目标是研究一种合理的机制，通过这种机制，典型的雄激素睾酮可能协调调节骨骼肌的合成代谢和分解代谢过程；即通过调节磷脂酰肌醇3-激酶（pi3 -激酶）/Akt信号通路。这将在一个跨学科团队的帮助下进行，该团队由具有雄激素生物学专业知识的发起人和在Akt和蛋白质翻译科学方面做出重大贡献的共同发起人组成。首先，在基于细胞的模型中，我将描述睾酮对pi3激酶、Akt和调节蛋白质翻译的关键效应激酶的调节。接下来，睾酮对这些分子靶点、肌肉质量和肌肉功能的影响将在一种新的条件、肌肉特异性Akt1过表达转基因小鼠中进行分析。最后，在一项正在进行的对睾酮水平低且行动受限的老年男性的睾酮管理研究中，将使用肌肉活检来研究人类雄激素作用的分子基础。除了赞助商和共同赞助商的支持外，波士顿医疗中心的环境提供了丰富的智力和技术资源，以确保该提案的成功和我作为独立研究者的发展。相关性：与年龄相关的肌肉质量损失与巨大的社会和经济成本相关。随着老年人口的持续增长，探索合成代谢疗法（如睾酮）促进肌肉生长的潜在机制是有价值的。潜在地，这项工作将有助于开发新的、更安全、更有效的治疗肌肉萎缩的方法。

DESCRIPTION (provided by applicant): I am in pursuit of this career development award to foster a translational research career focused on elucidating the mechanisms and developing strategies to attenuate skeletal muscle wasting. The age- and disease-related loss in muscle mass is associated with substantial social and economic costs and evidenced by impairments in strength, limitations in function, physical disability and loss of independence. Regrettably, there is a paucity of therapies to combat muscle wasting and the means by which existing therapeutics exert their effects remain poorly understood. The primary objective of this career development award is to investigate a plausible mechanism by which the prototypical androgen, testosterone, may coordinately regulate anabolic and catabolic processes in skeletal muscle; namely, through regulation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathway. This will be pursued with the help of an interdisciplinary team consisting of a sponsor with expertise in the biology of androgens, and co-sponsors who have made significant contributions to the science of Akt and protein translation. First, in cell-based models, I will characterize the regulation of PI3-kinase, Akt and key effector kinases that modulate protein translation, by testosterone. Next, the effects of testosterone on these molecular targets, muscle mass and muscle function will be analyzed in a novel conditional, muscle-specific Akt1 overexpressing transgenic mouse. Lastly, the molecular basis for androgen action will be investigated in humans using muscle biopsies acquired in an ongoing study of testosterone administration in older men with low testosterone levels and mobility limitations. In addition to the support of sponsors and co-sponsors, the environment at Boston Medical Center provides rich intellectual and technical resources to ensure the success of this proposal and my development as an independent investigator. Relevance: The age-related loss in muscle mass is associated with substantial social and economic costs. With the continued growth of our aged population, there is merit in exploring the underlying mechanisms by which anabolic therapies, such as testosterone, promote muscle growth. Potentially, this work will contribute to the development of novel, safer and more effective therapies for muscle wasting.