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

探究啮齿动物和人类的 ITGA11 信号传导，以用于肝纤维化的靶向抗纤维化治疗。

• 批准号: MR/P023541/1
• 负责人: Karen Piper Hanley
• 金额: $ 76.01万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP023541%2F1
• 关键词: Interrogating; ITGA11; signalling; rodent; human

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.

肝纤维化是一种破坏性的疤痕反应，由肝脏损伤（例如酒精或感染）引起。疤痕会损害肝功能。肝纤维化的最终治疗方法是肝移植。不幸的是，这是有限的，由于大量的人需要移植。因此，确定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。特征性瘢痕促进纤维化的进展。发现如何阻止疤痕产生或它如何向周围细胞发出信号，使纤维化永久化，这是一个非常有吸引力的治疗途径。我们已经确定，瘢痕信号通过细胞上的一种称为整合素α 11（ITGA 11）的受体来驱动和维持肝纤维化过程中的促纤维化信号。我们知道，细胞内ITGA 11信号传导的下游涉及P21激活激酶（PAK）蛋白家族，该蛋白家族可以被广泛抑制以改善小鼠的肝纤维化，但缺乏精确的机制细节;进一步翻译的障碍。因此，这些调查结果现在需要完善。为了进一步发展这个项目，我们将证明ITGA 11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一研究，在该模型中我们可以删除ITGA 11（例如，预期改善瘢痕形成），并使用新的成像分析，使我们能够真实的跟踪ITGA 11的精确功能位置和作用。我们将确定在肝纤维化过程中纤维化细胞内ITGA 11的确切信号传导，包括PAK，并利用这些知识来挖掘准确靶向单个分子而不是广泛蛋白质家族的治疗策略的潜力。为了促进这项工作的转化能力，重要的是，所有途径将直接在来自具有不同严重程度纤维化的患者的人类活检组织中进行验证，并在纤维化的原代人类培养模型中进行分子验证。总之，这些实验预计将证明ITGA 11在肝纤维化中的重要作用，并有助于确定在寻找迫切需要的抗纤维化疗法中有价值的新途径。

项目成果

Circadian Disruption Primes Myofibroblasts for Accelerated Activation as a Mechanism Underpinning Fibrotic Progression in Non-Alcoholic Fatty Liver Disease.

• DOI: 10.3390/cells12121582
• 发表时间: 2023-06-08
• 期刊: CELLS
• 影响因子: 6
• 作者: Jokl, Elliot;Llewellyn, Jessica;Simpson, Kara;Adegboye, Oluwatobi;Pritchett, James;Zeef, Leo;Donaldson, Ian;Athwal, Varinder S.;Purssell, Huw;Street, Oliver;Bennett, Lucy;Guha, Indra Neil;Hanley, Neil A.;Meng, Qing-Jun;Piper Hanley, Karen
• 通讯作者: Piper Hanley, Karen

SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis.

• DOI: 10.15252/emmm.201707860
• 发表时间: 2017-12
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Athwal VS;Pritchett J;Llewellyn J;Martin K;Camacho E;Raza SM;Phythian-Adams A;Birchall LJ;Mullan AF;Su K;Pearmain L;Dolman G;Zaitoun AM;Friedman SL;MacDonald A;Irving WL;Guha IN;Hanley NA;Piper Hanley K
• 通讯作者: Piper Hanley K

SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis

• DOI: 10.1038/s41598-018-36037-4
• 发表时间: 2018-12-17
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Athwal, Varinder S.;Pritchett, James;Hanley, Karen Piper
• 通讯作者: Hanley, Karen Piper

PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis.

PAK1 依赖性机械转导能够在纤维化过程中实现肌成纤维细胞核适应和染色质组织。

• DOI: 10.1016/j.celrep.2023.113414
• 发表时间: 2023
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Jokl E

Laser Capture and Deep Sequencing Reveals the Transcriptomic Programmes Regulating the Onset of Pancreas and Liver Differentiation in Human Embryos.

• DOI: 10.1016/j.stemcr.2017.09.018
• 发表时间: 2017-11-14
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Jennings RE;Berry AA;Gerrard DT;Wearne SJ;Strutt J;Withey S;Chhatriwala M;Piper Hanley K;Vallier L;Bobola N;Hanley NA
• 通讯作者: Hanley NA