Developing multi-level pipelines for senolytics discoveries

近年来，衰老细胞的积累被证明是大多数(如果不是全部)年龄相关疾病的驱动因素。选择性杀死衰老细胞的药物(感觉剂)在临床前研究中作为一系列与年龄相关的疾病的新治疗方式出现，第一代感受剂目前正在进行大约12项临床试验。翻译的主要限制是频繁的副作用，第一代抗衰老药物的有限的特异性，以及重要的是缺乏对给药方案的严格评估。领导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来发现新的更安全和更有效的抗衰老药物。该实验室利用人皮肤成纤维细胞的体外模型开发了一种新型的感觉剂筛选平台，并选择了一种有希望的候选药物进行临床前试验，使用在体小鼠模型。候选疗法被证明是安全的，能够带来通过脆弱指数、认知和神经肌肉功能评估的优异的抗衰老性能，一项专利申请正在进行中。该项目还计划将其应用于临床环境。该项目旨在通过在主管实验室建立的系统基础上开发多层次测试平台，进一步推进发现新型感光剂和其他具有抗衰老特性的试剂的管道。具体来说，该项目将(1)扩大体外筛选平台，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移植；(3)完善小鼠模型衰老表型的临床前评估方案。多层次平台不仅有助于更严格和具体地评估新药的影响，还将增加我们对哺乳动物衰老细胞生物学影响的了解。该项目将使用生物信息学和假设驱动的方法以及我们的行业合作伙伴(Novos Labs)提供的方法来测试和验证内部衍生的化合物。学生将获得与衰老和衰老研究相关的广泛技能方面的知识和经验。导师与健康老龄化联盟关系密切，这是一个由世界领先的老龄研究所组成的国际联盟；有各种工作坊、暑期学校、研讨会和会议供学生参加，并使他们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.