Investigating the role of SOX9 in liver fibrosis

研究 SOX9 在肝纤维化中的作用

• 批准号: MR/J003352/1
• 负责人: Karen Piper Hanley
• 金额: $ 57.78万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ003352%2F1
• 关键词: Investigating; role; SOX9; liver; fibrosis

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 at early stages of disease would be hugely beneficial. To achieve this better understanding of how the scar forms is needed. Although progress has been made in this area, unfortunately there are still no approved anti fibrotic treatments. To tackle this problem, I have identified SOX9 as a core factor responsible for mediating large components of scar formation. It is now essential to determine whether loss of SOX9 can be used as a means of reversing scar formation and ultimately fibrosis in the liver. This project will develop models to test whether loss of Sox9 prevents or ameliorates liver fibrosis and if over-expression of Sox9 worsens or accelerates the disease. In addition, I will discover what other genes lie downstream of SOX9 and integrate these with known signalling pathways important in liver fibrosis to uncover new targets and potential for therapies against liver fibrosis.Taken together, these experiments are anticipated to prove an important role for Sox9 in organ fibrosis and assist in identifying new pathways of value in the search for new 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，在疾病的早期阶段确定有效的抗纤维化治疗将是非常有益的。为了实现这一目标，需要更好地了解疤痕是如何形成的。虽然在这方面已经取得了进展，但不幸的是，仍然没有批准的抗纤维化治疗。为了解决这个问题，我已经将SOX 9确定为负责介导瘢痕形成的大部分的核心因子。现在必须确定SOX 9的丢失是否可以用作逆转肝脏瘢痕形成和最终纤维化的手段。该项目将开发模型来测试Sox 9的缺失是否可以预防或改善肝纤维化，以及Sox 9的过度表达是否会加速或加重疾病。此外，我还将发现SOX9下游的其他基因，并将这些基因与已知的肝纤维化重要信号通路整合，以发现新的靶点和抗肝纤维化治疗的潜力。总之，这些实验有望证明SOX9在器官纤维化中的重要作用，并有助于确定新的有价值的通路，以寻找新的治疗方法。

项目成果

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

The epigenomic landscape regulating organogenesis in human embryos linked to developmental disorders

调节与发育障碍相关的人类胚胎器官发生的表观基因组景观

• DOI: 10.1101/691766
• 发表时间: 2019
• 作者: Gerrard D

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

Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes.

• DOI: 10.1016/j.jhep.2014.10.016
• 发表时间: 2015-03
• 期刊: JOURNAL OF HEPATOLOGY
• 影响因子: 25.7
• 作者: Baxter, Melissa;Withey, Sarah;Harrison, Sean;Segeritz, Charis-Patricia;Zhang, Fang;Atkinson-Dell, Rebecca;Rowe, Cliff;Gerrard, Dave T.;Sison-Young, Rowena;Jenkins, Roz;Henry, Joanne;Berry, Andrew A.;Mohamet, Lisa;Best, Marie;Fenwick, Stephen W.;Malik, Hassan;Kitteringham, Neil R.;Goldring, Chris E.;Hanley, Karen Piper;Vallier, Ludovic;Hanley, Neil A.
• 通讯作者: Hanley, Neil A.

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