Novel Methodology for Identification of Senolytics that Reduce Age-related Disease and Dysfunction

描述(申请人提供)：慢性老龄化疾病在医疗保健支出中占很大比例，并导致数千万美国人和世界各地数亿人痛苦而有限的生活。递归制药公司开发了一个药物发现平台，该平台重新调整了治疗此类疾病的已知药物的用途。该平台包括高含量荧光图像分析，使用机器学习算法来识别在人类细胞中诱导的相关和目标变化，其中疾病和治疗已被建模。该系统已被用于筛选可能优先破坏衰老细胞的药物，因为这可能会导致组织功能的改善，并降低与衰老相关的病理和死亡率。在这个SBIR快速通道提案中，我们将：第一阶段确定各种人类细胞类型中衰老的形态特征。进展到第二阶段将取决于我们的能力，证明我们的形态学方法的能力，以识别衰老细胞独立于任何已知的衰老标记。第二阶段通过形态计量学方法确定优先破坏衰老细胞而不影响健康细胞的已知药物。评估已确定的感觉剂在小鼠各种组织功能和健康寿命模型中的效果。*在与年龄相关的心血管疾病的小鼠模型中，评估已确定的感觉剂的效果。递归制药公司拥有执行第一阶段/第二阶段快速通道SBIR提案的经验、工具和动力，并加快我们确定的任何化合物的商业开发。

DESCRIPTION (provided by applicant): Chronic diseases of aging account for a significant proportion of healthcare spending and result in a painful and limiting existence for many tens of millions of Americans and hundreds of millions of people around the world. Recursion Pharmaceuticals has developed a drug discovery platform that re-purposes known drugs for the treatment of such diseases. The platform consists of high content fluorescent image analysis using machine-learning algorithms to identify relevant and on-target changes induced in human cells in which diseases and treatments have been modeled. This system has been adapted to screen for drugs which may preferentially destroy senescent cells, as this may result in improved tissue function and decreases in pathology and mortality related to aging. In this SBIR fast-track proposal we will: PHASE I Identify a morphological profile of senescence in a variety of human cell types. Progression to Phase II will depend on our ability to demonstrate the power of our morphological approach to identify senescent cells independent of any known senescent markers. PHASE II Identify known drugs which preferentially destroy senescent cells, without affecting healthy cells, as identified by morphometric means. Evaluate the efficacy of identified senolytic agents in a variety of tissue function and health-span models in mice. *Evaluate the effect of identified senolytic agents in a murine model of age-associated cardiovascular disease. Recursion Pharmaceuticals has the experience, tools, and drive to execute this Phase I/Phase II Fast-track SBIR proposal, and to accelerate commercial development of any compounds we identify as a result.