Interrogating ITGA11 signalling in rodent and human for targeted anti-fibrotic therapy in liver fibrosis.
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
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.
Technical Summary
Fibrosis of the liver is characterised by progressive accumulation of ECM proteins and is a major cause of morbidity and mortality. End-stage liver fibrosis can be treated by liver transplantation, but this is limited by donor numbers. Anti-fibrotic therapies are an urgent priority, but no drugs have been approved to date. Pathological ECM and scarring drive progression of fibrosis. Discovering how to block scar production and the signalling in surrounding cells that perpetuates fibrosis represents a very attractive therapeutic avenue.
Cells contact the scar via cell surface integrin (ITG) receptors and signal intracellularly to mediate a broad range of cellular responses. We have identified ITGA11, and its partner subunit ITGB1, drives and perpetuates major pro-fibrotic signals in liver fibrosis. Moreover, intracellularly, downstream pathways involving P21-activated kinase (PAK) can be targeted pharmacologically to improve fibrosis in rodent models of liver fibrosis. The pressing challenges are now to test these data in vivo to determine the function and response of ITGA11 during liver fibrosis and if loss of ITGA11 prevents or ameliorates liver fibrosis. Moreover, we need determine the genome-wide effects of ITGA11 signalling to help identify new downstream pathways that may facilitate novel therapeutic intervention and interrogate the role of PAK to determine whether drugs already in development can be used as antifibrotic therapy in liver fibrosis. 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 organ fibrosis and assist in identifying new pathways of value in the search for new therapies.
Cells contact the scar via cell surface integrin (ITG) receptors and signal intracellularly to mediate a broad range of cellular responses. We have identified ITGA11, and its partner subunit ITGB1, drives and perpetuates major pro-fibrotic signals in liver fibrosis. Moreover, intracellularly, downstream pathways involving P21-activated kinase (PAK) can be targeted pharmacologically to improve fibrosis in rodent models of liver fibrosis. The pressing challenges are now to test these data in vivo to determine the function and response of ITGA11 during liver fibrosis and if loss of ITGA11 prevents or ameliorates liver fibrosis. Moreover, we need determine the genome-wide effects of ITGA11 signalling to help identify new downstream pathways that may facilitate novel therapeutic intervention and interrogate the role of PAK to determine whether drugs already in development can be used as antifibrotic therapy in liver fibrosis. 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 organ fibrosis and assist in identifying new pathways of value in the search for new therapies.
Planned Impact
Liver fibrosis is increasing in incidence and is a major cost to the NHS. It is associated with major morbidity and mortality. Largely, this problem comes from the lack of effective therapies at stages of the disease where the damage is reversible. This makes transplantation the last option and only then for lucky individuals where a donor organ is available. This research project will discover whether loss of the collagen binding integrin (integrin alpha-11; ITGA11) can ameliorate or reverse fibrosis and provide in depth insight into whether drug re-positioning for inhibition of and P21-activated kinase (PAK) is a realistic opportunity. It will discover new genes involved in liver fibrosis through identifying intracellular signalling pathways downstream of ITGA11 and it will place these in the context of known fibrosis pathways. Importantly, all data will be verified directly in human biopsy tissue from patients with varying severity of fibrosis and molecularly in primary human culture models of fibrosis. All of these steps will increase the likelihood of identifying new candidates for targeted drug development to treat liver fibrosis prior to end-stage disease. Therefore, this work carries substantial health and wealth implications.
Publications
Scott NA
(2023)
Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID.
in The European respiratory journal
Scott J
(2022)
Review article: epidemiology, pathogenesis and management of liver disease in adults with cystic fibrosis.
in Alimentary pharmacology & therapeutics
Rodrigues-Pinto R
(2018)
Human notochordal cell transcriptome unveils potential regulators of cell function in the developing intervertebral disc.
in Scientific reports
Raza S
(2021)
SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function.
in Science signaling
Purssell H
(2023)
The prevalence and burden of Rome IV bowel disorders of gut brain interaction in patients with non-alcoholic fatty liver disease: a cross-sectional study
in Scientific Reports
Martin K
(2021)
Genetic Contribution to Non-alcoholic Fatty Liver Disease and Prognostic Implications.
in Current diabetes reports
Lagan J
(2021)
Substrate for the Myocardial Inflammation-Heart Failure Hypothesis Identified Using Novel USPIO Methodology.
in JACC. Cardiovascular imaging
Jokl E
(2023)
PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis.
in Cell reports
Description | Chiesi medical grant in Cystic Fibrosis. "Investigating advanced diagnostics for liver related complications in cystic fibrosis". |
Amount | £25,942 (GBP) |
Organisation | Chiesi |
Sector | Private |
Country | Italy |
Start |
Description | Dean's Prize for clinical academics: Dr Varinder Athwal |
Amount | £250,000 (GBP) |
Organisation | University of Manchester |
Sector | Academic/University |
Country | United Kingdom |
Start |
Description | Guts UK (Charity) Development Grant. Investigating fibrosis pathobiology in cystic fibrosis related liver disease to improve clinical detection and management. |
Amount | £33,011 (GBP) |
Organisation | British Society of Gastroenterology |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start |
Description | Innovate UK, Life Sciences Industrial Strategy Challenge Fund on 'Integrated Diagnostics for Early Detection'. Integrated Diagnostics for the Early Detection of Liver Disease (ID_LIVER) |
Amount | £2,500,000 (GBP) |
Organisation | University of Manchester |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2020 |
End | 08/2023 |
Description | Interrogating mechanical signals in liver fibrosis for anti-fibrotic therapy; North West England MRC Fellowship in Clinical Pharmacology and Therapeutics |
Amount | £250,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2018 |
End | 09/2021 |
Description | MRC training support award |
Amount | £900 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2017 |
End | 12/2017 |
Description | Understanding the role of ITGA11 in renal fibrosis to advance diagnostic and therapeutic strategies |
Amount | £12,612 (GBP) |
Organisation | Kidneys for Life |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 02/2018 |
Title | ITGA11-venus lineage tracer mouse |
Description | This is a novel lineage tracing model to see where ITGA11 is during mouse development and disease |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2017 |
Provided To Others? | No |
Impact | Data not published yet. |
Description | Fibrotic mechanisms - Edinburgh |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Intellectual ideas and research planning. |
Collaborator Contribution | Material distribution. |
Impact | Manuscript published in Nature Comms 016. Direct collaborator included on current MRC project grant (2017-2020) |
Start Year | 2013 |
Description | BASL |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Invited lecture on work with collaborative discussion to follow. |
Year(s) Of Engagement Activity | 2017 |
Description | Keystone meeting Session Chair |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Session Chair ' Core Mechanisms versus Organ Specific Mediators of Fibrosis' . Keystone meeting Fibrosis and Tissue Repair, British Columbia, Canada. |
Year(s) Of Engagement Activity | 2020 |
Description | Semiar at BASL Basic Science Retreat |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Seminar on: Tissue stiffness, actin dynamics and the profibrotic response of HSCs |
Year(s) Of Engagement Activity | 2018 |
Description | Semiar invite Institute of Hepatology, King's College London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation on my work on Matrix deposition and mechanosignaling in HSCs during liver fibrosis |
Year(s) Of Engagement Activity | 2018 |
Description | Seminar at UPenn (on line) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Seminar at UPenn followed by data discussion and on-going interaction |
Year(s) Of Engagement Activity | 2021 |
Description | Talk in industry at UCB London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk on fibrosis to industry - discussions on developing reagents for use in models. |
Year(s) Of Engagement Activity | 2017 |