Defining a role for non-canonical mTORC1 activity at focal adhesions

定义非典型 mTORC1 活性在粘着斑中的作用

• 批准号: BB/Y001427/1
• 负责人: Bernadette Carroll
• 金额: $ 58.88万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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=BB%2FY001427%2F1
• 关键词: Defining; role; non; canonical; mTORC1

Rapamycin is a drug that was originally isolated from bacteria collected on Easter Island, also known as Rapa Nui. It specifically inhibits the mechanistic Target Of Rapamycin Complex 1 (mTORC1), an evolutionarily conserved protein complex that integrates mitogenic and stress signals to control cell growth and metabolism. Since its discovery forty years ago, rapamycin has been used extensively for its immunosuppressive and antitumour properties. More recently however, it has gained attention as a promising anti-ageing drug. Work in laboratory 'animal' models, such as yeast, flies, fish and mice has shown that treatment with rapamycin has similar effects to caloric restriction which is one of the most robust interventions to promote healthspan and lifespan. Rapamycin treatment in humans is however associated with a number of poorly understood side effects, including impaired wound healing. Such side-effects limit the feasibility of using rapamycin to support healthy human ageing. In this study, we want to explore the role and regulation of a specific pool of mTORC1 that we have identified. Our recent manuscript described, for the first time, that mTORC1 can be activated at the cell edge, in close proximity to proteins associated with focal adhesions (Rabanal-Ruiz et al, 2021). These are specialist structures responsible for anchoring cells to the extracellular environment. The dynamic nature of these structures is important during cell migration, one of the earliest stages of wound healing to close the wound off to the outside environment. Our preliminary and published data indicates that there is tight reciprocal regulation of mTORC1 activity and focal adhesions; namely, disruption of focal adhesions impairs mTORC1 activation while conversely, inhibition of mTORC1 leads to changes in focal adhesion number, size and localisation. Furthermore, our work indicates that this specific pool of mTORC1 is not controlled via classical regulators, and thus we want to identify exactly how it is controlled. Given the detrimental impact of rapamycin on wound healing, we propose that the pool of mTORC1 in the vicinity of focal adhesions plays an important and specific role in this process. The aim of this grant is to therefore identify the mechanisms controlling mTORC1 at focal adhesions and determine its physiological role in cell migration and wound healing. These data may inform on the future development of therapeutic options to mitigate the side-effects of rapamycin, allowing its widespread use a healthy ageing intervention.

雷帕霉素是一种药物，最初是从复活节岛（也称为拉帕努伊）收集的细菌中分离出来的。它特异性抑制雷帕霉素靶点复合物 1 (mTORC1)，这是一种进化上保守的蛋白质复合物，可整合促有丝分裂和应激信号来控制细胞生长和代谢。自四十年前被发现以来，雷帕霉素因其免疫抑制和抗肿瘤特性而被广泛使用。然而最近，它作为一种有前途的抗衰老药物而受到关注。对酵母、苍蝇、鱼和小鼠等实验室“动物”模型的研究表明，雷帕霉素治疗与热量限制具有相似的效果，热量限制是促进健康和寿命的最有力的干预措施之一。然而，雷帕霉素对人类的治疗与许多鲜为人知的副作用有关，包括伤口愈合受损。这些副作用限制了使用雷帕霉素支持人类健康衰老的可行性。在这项研究中，我们想要探索我们已确定的特定 mTORC1 池的作用和调节。我们最近的手稿首次描述了 mTORC1 可以在细胞边缘被激活，靠近与粘着斑相关的蛋白质（Rabanal-Ruiz 等人，2021）。这些是负责将细胞锚定到细胞外环境的特殊结构。这些结构的动态性质在细胞迁移过程中非常重要，细胞迁移是伤口愈合的最早阶段之一，目的是使伤口与外部环境隔绝。我们的初步和已发表的数据表明，mTORC1 活性和粘着斑存在严格的相互调节；也就是说，粘着斑的破坏会损害 mTORC1 的激活，而相反，mTORC1 的抑制会导致粘着斑数量、大小和定位的变化。此外，我们的工作表明，mTORC1 的这个特定库不受经典调节器的控制，因此我们希望准确确定它是如何控制的。考虑到雷帕霉素对伤口愈合的不利影响，我们认为粘着斑附近的 mTORC1 库在此过程中发挥着重要且特定的作用。因此，这项资助的目的是确定控制粘着斑处 mTORC1 的机制，并确定其在细胞迁移和伤口愈合中的生理作用。这些数据可能为减轻雷帕霉素副作用的治疗方案的未来发展提供信息，从而使其广泛用于健康的衰老干预。