Cellular senescence and regeneration in the epithelia: novel mechanisms and therapeutic approaches

英国人口正在老龄化。2019年，65岁及以上人口为1230万人。到2066年，这一数字预计将达到2040万（占英国总人口的26%）。我们的寿命比人类历史上任何时候都要长，但这一公共卫生的胜利伴随着一个不幸的副作用：与年龄有关的慢性疾病的新流行病仍然难以治愈。我想通过针对其主要机制——细胞衰老——来对抗老年性疾病。衰老细胞在老化的皮肤和其他上皮中积累，增加炎症并促进组织损伤。不可避免的后果是，老化的皮肤不能有效地修复，更容易受到损伤和疾病。自第一次世界大战以来，这种衰老的现实就被记录下来，观察到年长士兵的伤口愈合得更慢，而胎儿的皮肤伤口愈合得更慢，没有疤痕。我的项目旨在彻底改变目前对衰老的看法——衰老是一个不可改变的、不可避免的过程——并提供新的工具来增加皮肤的再生，提高生活质量，促进下一代的“健康寿命”。在我的小组中，我们将研究：(i)皮肤衰老的分子机制，以详细了解这一现象。我的初步数据表明，皮肤的衰老与初级纤毛的丧失有关，初级纤毛是高度专业化的天线，对再生至关重要。我的目标是了解皮肤衰老是从哪里开始的，它是如何开始的，以及针对初级纤毛的针对性干预是否可以增加皮肤再生。（ii）利用一种新的模型：多刺小鼠来预防衰老和加速皮肤再生。非洲多刺鼠能够脱落高达60%的背部皮肤以避免捕食。然而，与其他哺乳动物不同的是，这种刺可以再生皮肤、肌肉、软骨甚至头发，几乎没有纤维化的迹象。我的目标是了解哪些途径负责这种无纤维化伤口愈合，并将结果应用于改善人类皮肤再生。（iii）诊断以确定最佳治疗窗口和潜在的临床干预措施。确定何时针对某种疾病与治疗本身同样重要。正如我在我目前的生物传感器公司（http://sensibile.co）所做的那样。uk/)，我们在移植前检测供体器官的衰老生物特征，我的目标是确定皮肤的衰老水平。通过这样做，我们可以确定老年患者接受手术治疗的风险，或者将有趣的结果应用于美容目的，增加实验室和爱丁堡大学的转化和创业机会。最后，我坚信伟大的科学需要伟大的团队。我的首要任务是为我的团队提供最好的体验，同时考虑到他们的多样性，建立一个能够促进创造力和创新的包容性团队。正如我对所有学生所做的那样，特别是在COVID-19大流行期间，我的目标不仅是提供技术专业知识，而且提供成长为科学家的机会，并在他们需要时提供个人帮助。研究诚信、负责任的创新、多样性和包容性将是我实验室的核心，以提供出色的研究和独特的转化机会。

The UK population is ageing.In 2019, 12.3 million people were aged 65 or over. By 2066 this number is estimated to reach 20.4 million (26% of all UK population). We are living longer than at any time in human history, but this victory of public health is accompanied by an unfortunate side-effect: a new epidemic of chronic, age-associated diseases for which cures remain elusive. I want to combat age-onset disease by targeting its main mechanism: cellular senescence.Senescent cells accumulate in aged skin and other epithelia, increasing inflammation and promoting tissue damage. The inevitable consequence is that old skin is not as efficient at repair and is more susceptible to damage and disease. This reality of ageing has been documented since World War I, with the observation that wounds heal more slowly in older soldiers whereas the fetus heals cutaneous wounds without a scar.My projects aim to revolutionize the current perception of senescence -as an immutable, inevitable process- and provide new tools to increase regeneration in the skin, improving the quality of life, and promoting ''healthspan'' for the next generation.In my group we will investigate:(i) The molecular mechanisms of senescence in the skin to understand in detail this phenomenon. My preliminary data suggest that senescence onset in the skin is linked to the loss of primary cilia, highly specialized antennas that are crucial for regeneration. I aim to understand where senescence starts in the skin, how it starts, and if targeted interventions towards the primary cilia can increase skin regeneration.(ii) Novel targets to prevent senescence and accelerate skin regeneration using a novel model: the spiny mouse. The african spiny mouse is able to shed up to 60% of its back's skin to avoid predation. However, unlike other mammalians, the spiny can regrow the skin, muscle, cartilage and even hair, with minimal signs of fibrosis. I aim to understand which pathways are responsible for this fibrosis-free wound healing and apply the results to improve skin regeneration in humans.(iii) Diagnostics to identify the best therapeutic window and potential clinical interventions. Defining WHEN to target a condition is as equally important as the treatment itself. As I have done with my current biosensor company (http://sensibile.co.uk/), where we detect senescence biosignatures in donor organs before transplant, I aim to determine the levels of senescence in skin. By doing so, we could determine the risk of older patients undergoing surgical treatment, or apply interesting results to cosmetic purposes, increasing the translational and entrepreneurial opportunities for the laboratory and the University of Edinburgh.Finally, I firmly believe that great science requires a great team. My priority would be to provide the best experience to my team, taking into account their diversities, to establish an inclusive group that can foster creativity and innovation. As I have been doing with all my students, especially during the COVID-19 pandemic, I aim to provide not only technical expertise, but also an opportunity to grow as scientists, and personal help should they require it. Research integrity, responsible innovation, diversity and inclusion will be the core of my lab, to deliver outstanding research and unique translational opportunities.