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

上皮细胞衰老和再生：新机制和治疗方法

• 批准号: MR/X033155/1
• 负责人: Sofia Ferreira-Gonzalez
• 金额: $ 252.57万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX033155%2F1
• 关键词: Cellular; senescence; regeneration; epithelia; novel

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.

英国人口正在老龄化。2019年，有1230万人年龄在65岁或以上。到2066年，这一数字估计将达到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，但公共卫生的这一胜利也伴随着一个不幸的副作用：一种新的慢性、与年龄有关的疾病的流行病，而这种疾病的治愈方法仍然难以捉摸。我想通过针对其主要机制来对抗年龄发病性疾病：细胞衰老。衰老细胞积累在老化的皮肤和其他上皮细胞中，增加炎症并促进组织损伤。不可避免的后果是，老化的皮肤修复效率不高，更容易受到损伤和疾病的影响。自第一次世界大战以来，衰老的现实就被记录下来，观察到年长士兵的伤口愈合较慢，而胎儿愈合皮肤伤口时没有疤痕。我的项目旨在彻底改变目前对衰老的看法-作为一个不可改变的，不可避免的过程-并提供新的工具来增加皮肤再生，提高生活质量，并促进下一代的“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从哪里开始，它是如何开始的，以及对初级纤毛的有针对性的干预是否可以增加皮肤再生。(ii)新的目标，以防止衰老和加速皮肤再生的新模型：多刺小鼠。非洲多刺鼠背部60%的皮肤可以脱落，以避免被捕食。然而，与其他非洲人不同的是，刺可以再生皮肤，肌肉，软骨甚至头发，纤维化的迹象很小。我的目标是了解哪些途径负责这种无纤维化的伤口愈合，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。确定何时针对一种疾病与治疗本身同样重要。正如我在目前的生物传感器公司（http：//sensibile.co.uk/）所做的那样，我们在移植前检测捐赠器官中的衰老生物特征，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，为实验室和爱丁堡大学增加翻译和创业机会。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经验，考虑到他们的困难，建立一个包容的团队，可以培养创造力和创新。正如我一直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长，而且是作为科学家成长的机会，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。