High throughput functional screening of anti-sarcopenia therapeutics

肌肉减少症是一种与年龄相关的骨骼肌质量和功能的进行性损失，与福尔斯、骨折、抑郁、营养不良、住院时间延长和死亡的风险增加相关。仅在美国，这种疾病的年度住院费用就为404亿美元，约占年度总支出的4%，使其成为重大的公共卫生负担。然而，没有FDA批准的肌肉减少症治疗方法。需要使用老年啮齿类动物或其组织进行化合物筛选，这对这种疾病的药物发现构成了实质性障碍。相比之下，线虫秀丽隐杆线虫为高通量抗少肌症药物发现提供了更适合的模型系统。随着年龄的增长，蠕虫显示出肌肉结构和功能的逐渐丧失，导致动物进入以最小的身体运动为特征的衰老状态，直到它们最终死亡。初步数据显示，衰老状态与肌肉力量的损失密切相关，提供了适合高通量筛选的终点。在初步数据的基础上，这项申请有两个目的。在Aim1中，我们将开发一种新的高通量人工智能辅助工作流程，将动物分类为健康、衰老或死亡状态。将获得图像库，并将实施姿势估计算法，以开发一种快速方法来量化老年人群中衰老动物的百分比。在目标2中，我们将使用已知延长寿命的化合物库进行初步筛选，使用衰老和动物活动作为终点。我们假设，一些抗衰老化合物也将改善健康寿命，因此提供了一种新的肌肉减少症治疗方法。为了直接验证这些命中，我们将测量老年动物肌肉力量的改善以及肌节和线粒体网络的完整性。我们预计我们的筛选框架将成为未来筛选用于肌肉减少症治疗的化合物库的基础。除了拟议的研究调查，这一应用程序将奠定基础的PI的创业生涯的发展。PI是筛选管道中使用的两项基础技术的共同发明者，并共同创立了一家初创公司。PI的目标是过渡到业务和商业化的筛选技术。已经确定了具有重要业务专长的导师，与他们的合作将使PI能够在首席技术官的角色中成长。PI制定了一项职业发展计划，旨在建立商业技能，老年科学研究和人工智能方面的专业知识，并通过在线课程的入学和参加这些领域的顶级会议来支持。一个由商业专家和世界级学者组成的团队已经聚集在一起，指导和锚PI的创业生涯在一家创业公司，专注于改善老年人的健康寿命。

Sarcopenia is a progressive age-related loss of skeletal muscle mass and function associated with an increased risk of falls, fractures, depression, malnutrition, prolonged hospital stays, and death. The annual hospitalization costs of this disease in the US alone are $40.4 billion, ~4% of the total yearly expenditure, making it a significant public health burden. Yet, there are no FDA-approved treatments for sarcopenia. The need to use aged rodents or their tissues for compound screens poses a substantial barrier to drug discovery for this disease. In contrast, the nematode Caenorhabditis elegans provides a more amenable model system for high-throughput anti- sarcopenia drug discovery. The worm shows progressive loss of muscle structure and function as it ages, leading to animals entering a state of decrepitude characterized by minimal body movement until they finally die. Preliminary data shows that the decrepitude state strongly correlates with the loss of muscle strength, providing an endpoint amenable to high throughput screening. Building on the preliminary data, this application has two aims. In Aim1, we will develop a new high-throughput AI-assisted workflow to classify animals into healthy, decrepit, or dead states. Image libraries will be acquired and pose-estimation algorithms will be implemented to develop a fast methodology to quantify the percentage of decrepit animals in an aged population. In Aim 2, we will perform a primary screen with a library of compounds known to extend lifespan using decrepitude and animal activity as endpoints. We hypothesize that some of the anti-aging compounds will also improve healthspan and therefore provide a novel source of therapeutics for sarcopenia. To directly validate these hits, we will measure improvements in muscle strength and the integrity of sarcomeres and mitochondria networks in aged animals. We anticipate our screening framework will become the basis for future screening of compound libraries for sarcopenia treatment. In addition to the proposed research investigations, this application will lay the foundation for the entrepreneurial career development of the PI. The PI is the co-inventor of the two foundational technologies used in the screening pipeline and has co-founded a startup company. The PI aims to transition into the business and commercialize the screening technologies. Mentors with significant business expertise have been identified, and engagement with them will enable the PI to grow in his role as the Chief Technology Officer. The PI has developed a career development plan that aims to build expertise in business skills, geroscience research, and AI, which is supported by enrollment in online courses and attendance at premier conferences in these areas. A team of business experts and world-class academicians has been assembled to mentor and anchor the entrepreneurial career of the PI in a startup company that is focused on improving the healthspan of the elderly.