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.

英国人口正在老化。在2019年，有1,230万人年龄在65岁或以上。到2066年，这个数字估计达到了2040万（占英国所有人口的26％）。我们的寿命比人类历史上的任何时候都长，但是公共卫生的这一胜利伴随着不幸的副作用：一种慢性，相关疾病的新流行病仍然难以捉摸。我想通过靶向其主要机制来打击年龄发作的疾病：细胞衰老。肾上腺细胞积聚在衰老的皮肤和其他上皮中，增加炎症并促进组织损伤。不可避免的结果是，旧皮肤在修复方面的效率不高，并且更容易受到损害和疾病的影响。自第一次世界大战以来，这种衰老的现实已被记录在记录中，观察到伤口在年长的士兵中的愈合较慢，而胎儿在没有疤痕的情况下治愈皮肤伤口。 - 并提供新的工具来增加皮肤的再生，改善生活质量并为下一代促进“ HealthSpan”。在我的小组中，我们将研究：（i）皮肤中衰老的分子机制以了解详细说明这一现象。我的初步数据表明，皮肤中的衰老开始与原发性纤毛的丧失有关，纤毛的丧失，高度专业的天线对于再生至关重要。我的目的是了解衰老在皮肤中的何处，如何开始，如果针对原发性纤毛的靶向干预措施可以增加皮肤再生。（ii）使用新型模型：刺刺小鼠防止衰老和加速皮肤再生的新型靶标。这款非洲小鼠能够脱落多达60％的背部皮肤，以避免捕食。然而，与其他哺乳动物不同，刺可以使皮肤，肌肉，软骨甚至头发再生，并具有最小的纤维化迹象。我的目的是了解哪些途径是导致这种无纤维化伤口愈合的原因，并应用结果以改善人类的皮肤再生。（iii）诊断以识别最佳的治疗窗口和潜在的临床干预措施。定义何时靶向疾病与治疗本身同样重要。正如我与目前的生物传感器公司（http://sensibile.co.uk/）所做的那样，我们在移植前发现了供体器官中的衰老生物签名，我旨在确定皮肤中衰老的水平。通过这样做，我们可以确定接受手术治疗的老年患者的风险，或将有趣的结果应用于美容目的，增加了实验室和爱丁堡大学的转化和企业家的机会。我坚信，伟大的科学需要一项伟大的科学团队。我的首要任务是考虑到他们的多样性，为我的团队提供最佳体验，以建立一个可以促进创造力和创新的包容性群体。当我与所有学生（尤其是在Covid-19的大流行期间）所做的那样，我的目标不仅提供技术专长，而且还提供一个成长为科学家的机会，如果他们需要的话，个人的帮助。研究完整性，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。