RelA Serine 536 phosphorylation as a selective therapeutic target in fibrotic disease.
Lead Research Organisation:
Newcastle University
Department Name: Institute of Cellular Medicine
Abstract
It is estimated that fibrosis is an underlying cause of up to 40% of all deaths in the western world. Fibrosis or tissue scarring caused by chronic injury can occur in many organs including; liver, lung, kidney and skin. Specifically for liver disease over 12,000 people die every year in the UK and these figures will continue to rise due to increased obesity related liver disease, excess alcohol consumption and hepatitis infection. Currently there are no proven effective anti-fibrotic drugs therefore transplantation is the only alternative for patients where the underlying cause of disease can not be treated. Therefore liver fibrosis is and will continue to be a major financial and healthcare burden on the NHS. This project aims to inhibit a specific modification of a protein in the scar promoting cells that promotes their survival. Once scar producing cells are removed from the liver the scar can be degraded and disease progression will be prevented. I aim to understand is the signalling events regulating this modification and to test if inhibiting it will reverse fibrosis. Finally I will establish whether this is a critical signalling event that promotes survival of scar forming cells in organs which are susceptible to fibrosis i.e. lung, kidney and skin.
Technical Summary
The vision for this project is to therapeutically exploit a specific post translational modification of the RelA subunit of NF-kB to treat organ fibrosis. I aim to discover if RelA serine 536 phosphorylation (P-Ser536-RelA) is a genuine anti-fibrotic target and a predictive indicator of fibrosis which will regress after
pharmacological blockade of the renin-angiotensin II system (RAS). This work is based on my recent observations that constitutive P-Ser536-RelA is a characteristic of both rodent and human hepatic myofibroblasts (HM) linked with their survival and fibrosis. I discovered that HM P-Ser536-RelA is under autocrine control of the RAS and that inhibition of this pathway in two rodent models of liver fibrosis was associated with reduced P-Ser536-RelA and regression of disease. This mark was highly expressed in cirrhotic Hepatitis C patients and was a predictive indicator of patients whose fibrosis will regress in response to treatment with losartan. However, many questions remain, as not all of the patients in this study responded to losartan treatment despite P-Ser536-RelA being present. This suggests the existence of other P-Ser536-RelA signalling mechanisms in myofibroblasts. Functional biochemistry defining the signalling pathways which induce P-Ser536-RelA and direct targeting of this modification in vivo are now required. Quantifying the expression levels and localisation of P-Ser536-RelA in human diseased tissue from multiple fibrotic disorders is required to show that it has potential to be a generic anti-fibrotic target. In this project I will determine if P-Ser536-RelA in human HM is a critical integrator of damage associated signals and if it promotes HM survival in different types of liver disease. I will use cell permeable serine 536 phosphorylation competing peptides to selectively target this event in three progressive in vivo models of liver damage to prove that this will be an effective anti-fibrotic strategy in fibrosis where injury persists, as this parallels the clinical problem. To elucidate if this modification in myofibroblasts is a common signalling event that promotes their survival in organ fibrosis P-Ser536-RelA associated with myofibroblasts will be quantified in biopsy slides from lung, kidney and skin fibrosis. To further translate my discoveries on NF-kB to fibrogenesis in other organs, I will determine if RAS inhibits and P-Ser536-RelA competing peptides can influence the phenotype and lifespan of human lung (myo)fibroblasts. This work will further our understanding of common mechanisms which underpin the pathogenesis of fibrotic disease and could potentially be developed as a generic anti-fibrotic target.
pharmacological blockade of the renin-angiotensin II system (RAS). This work is based on my recent observations that constitutive P-Ser536-RelA is a characteristic of both rodent and human hepatic myofibroblasts (HM) linked with their survival and fibrosis. I discovered that HM P-Ser536-RelA is under autocrine control of the RAS and that inhibition of this pathway in two rodent models of liver fibrosis was associated with reduced P-Ser536-RelA and regression of disease. This mark was highly expressed in cirrhotic Hepatitis C patients and was a predictive indicator of patients whose fibrosis will regress in response to treatment with losartan. However, many questions remain, as not all of the patients in this study responded to losartan treatment despite P-Ser536-RelA being present. This suggests the existence of other P-Ser536-RelA signalling mechanisms in myofibroblasts. Functional biochemistry defining the signalling pathways which induce P-Ser536-RelA and direct targeting of this modification in vivo are now required. Quantifying the expression levels and localisation of P-Ser536-RelA in human diseased tissue from multiple fibrotic disorders is required to show that it has potential to be a generic anti-fibrotic target. In this project I will determine if P-Ser536-RelA in human HM is a critical integrator of damage associated signals and if it promotes HM survival in different types of liver disease. I will use cell permeable serine 536 phosphorylation competing peptides to selectively target this event in three progressive in vivo models of liver damage to prove that this will be an effective anti-fibrotic strategy in fibrosis where injury persists, as this parallels the clinical problem. To elucidate if this modification in myofibroblasts is a common signalling event that promotes their survival in organ fibrosis P-Ser536-RelA associated with myofibroblasts will be quantified in biopsy slides from lung, kidney and skin fibrosis. To further translate my discoveries on NF-kB to fibrogenesis in other organs, I will determine if RAS inhibits and P-Ser536-RelA competing peptides can influence the phenotype and lifespan of human lung (myo)fibroblasts. This work will further our understanding of common mechanisms which underpin the pathogenesis of fibrotic disease and could potentially be developed as a generic anti-fibrotic target.
