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

描述（由申请人提供）：老年慢性疾病占医疗保健支出的很大一部分，并导致数千万美国人和世界各地数亿人的痛苦和限制性生活。Recursion Pharmaceuticals开发了一个药物发现平台，重新利用已知药物治疗此类疾病。该平台包括使用机器学习算法的高内容荧光图像分析，以识别在人类细胞中诱导的相关和靶向变化，其中疾病和治疗已被建模。该系统已被适配为筛选可能优先破坏衰老细胞的药物，因为这可能导致改善组织功能并降低与衰老相关的病理学和死亡率。在这个SBIR快速通道的建议，我们将：第一阶段确定在各种人类细胞类型的衰老形态学概况。进展到II期将取决于我们证明我们的形态学方法独立于任何已知的衰老标记物鉴定衰老细胞的能力。 第二阶段鉴定已知的药物，优先破坏衰老细胞，而不影响健康细胞，如通过形态测定方法鉴定的。 在小鼠的各种组织功能和健康寿命模型中评价已鉴定的衰老清除剂的功效。* 评估鉴定的衰老清除剂在年龄相关性心血管疾病的鼠模型中的作用。Recursion Pharmaceuticals拥有执行I期/II期快速SBIR提案的经验、工具和动力，并加速我们因此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.