Interrogating ITGA11 signalling in rodent and human for targeted anti-fibrotic therapy in liver fibrosis.

肝纤维化是一种破坏性的疤痕反应，由肝脏损伤(如酒精或感染)引起。疤痕会损害肝功能。肝纤维化的最终治疗方法是移植。不幸的是，由于需要移植的人数很多，这一数字有限。出于这个原因，找到有效的抗纤维化治疗方法将是非常有益的，因为目前还没有。特有的疤痕促进了纤维化的进展。发现如何阻止疤痕的产生，或者它如何向周围细胞发出信号，使纤维化永久化，这是一条非常有吸引力的治疗途径。我们已经确认，在肝纤维化过程中，瘢痕信号通过细胞上一种名为整合素α11(ITGA11)的受体来驱动和维持促纤维化信号。我们知道，ITGA11下游的细胞内信号涉及P21激活的激酶(PAK)蛋白家族，该蛋白家族可以广泛抑制以改善小鼠的肝纤维化，但缺乏确切的机制细节；这是进一步翻译的障碍。因此，这些发现现在需要改进。为了进一步发展这个项目，我们将证明ITGA11在肝纤维化中的重要作用。我们将直接在纤维化小鼠模型中进行这项工作，在这些模型中，我们可以删除ITGA11(例如，预期可以改善瘢痕形成)，并使用新的成像分析，使我们能够实时跟踪ITGA11的准确功能位置和作用。我们将确定包括PAK在内的肝纤维化过程中肝纤维化细胞内ITGA11的确切信号，并利用这一知识来发掘准确针对单个分子而不是广泛的蛋白质家族的治疗策略的可能性。为了促进这项工作的翻译能力，重要的是，所有通路都将直接在不同严重程度的纤维化患者的人体活检组织中进行验证，并在最初的人类纤维化培养模型中进行分子验证。综上所述，这些实验有望证明ITGA11在肝纤维化中发挥重要作用，并在寻找迫切需要的抗纤维化治疗方面帮助确定新的有价值的途径。

Liver fibrosis is a devastating scarring reaction that results from injury to the liver (e.g. by alcohol or infection). The scarring impairs liver function. The ultimate treatment of liver fibrosis is transplantation. Unfortunately this is limited due to the high numbers of people in need of a transplant. For this reason, identifying effective anti-fibrotic treatments for the disease would be hugely beneficial as none currently exist. The characteristic scar promotes progression of fibrosis. Discovering how to block scar production or how it signals to surrounding cells that perpetuates fibrosis represents a very attractive therapeutic avenue. We have identified that the scar signals through a receptor on cells called integrin alpha 11 (ITGA11) to drive and perpetuate pro-fibrotic signals during liver fibrosis. We know that downstream of ITGA11 signalling within the cell involves P21-activated kinase (PAK) protein family that can be broadly inhibited to improve liver fibrosis in mice but lack the precise mechanistic detail; a barrier to further translation. As a result, these findings now require refinement. To develop this project further we will prove the important role of ITGA11 in liver fibrosis. We will do this directly in mice models of fibrosis in which we can delete ITGA11 (e.g. anticipated to improve scarring) and using novel imaging analysis allowing us to track the precise functional location and role of ITGA11 in real time. We will determine the exact signalling of ITGA11 inside fibrotic cells during liver fibrosis, including PAKs, and use this knowledge to unpick the potential for therapeutic strategies which accurately targets individual molecules rather than broad protein families. To facilitate the translational capability of this work, importantly, all pathways will be verified directly in human biopsy tissue from patients with varying severity of fibrosis and molecularly in primary human culture models of fibrosis. Taken together, these experiments are anticipated to prove an important role for ITGA11 in liver fibrosis and assist in identifying new pathways of value in the search for urgently needed anti-fibrotic therapies.