Developing multi-level pipelines for senolytics discoveries

近年来，衰老细胞的积累已被证明是大多数（如果不是所有）与年龄相关的疾病的驱动因素。选择性杀死衰老细胞的药物（senolytics）在临床前研究中成为广泛的年龄相关疾病的新型治疗方式，第一代senolytics现在正在进行大约十几项临床试验。翻译的主要限制是频繁的副作用，第一代senolytics有限的特异性，以及重要的是缺乏严格的评估管理协议。首席主管的实验室一直致力于利用细胞衰老和细胞能量学的知识和专业知识发现新的更安全和更有效的senolytics。该实验室开发了一种新型的senolytics筛选平台，使用人皮肤成纤维细胞进行体外模型，并选择了一种有前途的候选药物进行体内小鼠模型的临床前试验。候选治疗被证明是安全的，能够带来优异的抗衰老性能，通过脆弱指数，认知和神经肌肉功能评估，专利申请正在进行中。该项目旨在通过在首席主管实验室建立的系统基础上开发一个多层次的测试平台，进一步推进发现新的senolytics和其他具有抗衰老特性的药物的管道。具体而言，该项目将（1）扩展体外筛选平台，使用不同的细胞类型，生长条件和治疗方案（2）建立体外3D模型测试平台，使用3D皮肤模型和人类皮肤外植体（3）完善小鼠模型中衰老表型的临床前评估方案。该多层次平台不仅有助于更严格、更具体地评估新型药物的作用，还有助于我们更深入地了解衰老细胞对哺乳动物衰老的生物学影响。该项目将测试和验证使用生物信息学和假设驱动方法以及我们的行业合作伙伴（Novos Labs）提供的方法在内部衍生的化合物。学生将获得与衰老和衰老研究相关的广泛技能的知识和经验。主管与健康老龄化联盟密切相关，该联盟是世界领先的老龄化研究所的国际联合会;有各种讲习班、暑期学校、研讨会和会议供学生参加，并接触到高度刺激的学习环境。

Accumulation of senescent cells has been shown in recent years as a driver of most, if not all age-associated conditions. Drugs that selectively kill senescent cells (senolytics) emerged as novel therapeutic modalities for a wide range of age-associated diseases in pre-clinical studies, and first generation senolytics are now in about a dozen of clinical trials. The main limitations for translation are frequent side effects, limited specificity of first-generation senolytics, and importantly the lack of rigorous evaluations of the administration protocols.Lead supervisor's lab has been engaged in the discovery of novel safer and more effective senolytics using knowledge and expertise in cell senescence and cellular energetics. The lab has developed a novel senolytics screening platform with an in vitro model using human dermal fibroblasts, and one promising candidate has been selected for pre-clinical tests using an in vivo mouse model. The candidate treatment was shown to be safe and able to bring about excellent anti-ageing properties assessed by frailty index, cognitive and neuromuscular function, and a patent application is in process. Its application to clinical setting is also being planned.The project aims to further advancing a pipeline for discovery of novel senolytics and other agents with anti-ageing properties by developing a multi-level testing platform, based on the systems established at the lead supervisor's lab. Specifically, the project will (1) expand the in vitro screening platform, using different cell types, growth conditions, and treatment schedules (2) establish an in vitro 3D model testing platform, using 3D skin models and human skin explants and (3) refine the pre-clinical assessment protocols for ageing phenotype in mouse models. The multi-level platforms will benefit not only the ability to more rigorously and specifically assess the effects of novel agents, but also increase our understanding of the biological impact of senescent cells in mammalian ageing.The project will test and validate compounds derived in-house using bioinformatic and hypothesis driven approaches as well as those provided by our industry partner (Novos Labs). The student will obtain knowledge and experiences in a wide range of skills associated with ageing and senescence research. The supervisor is closely associated with the Alliance for Healthy Ageing, an international consortium of world-leading ageing institutes; there are a variety of workshop, summer schools, seminars and meetings for the student to attend and to be exposed to highly stimulating learning environments.