Fibrillin-1 regulation of TGFbeta bioavailability

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

Transforming growth factor (TGF) beta is a potent growth factor that regulates cell survival, proliferation, migration and differentiation. Understanding TGFbeta signalling dysregulation in severe heritable diseases such as Marfan syndrome, and in chronic fibrotic disorders such as sclerosis is a major challenge in the search for effective therapies. We have discovered that fibrillin-1 regulates TGFbeta1 bioavailability by releasing latent TGFbeta from the extracellular matrix. This application is to build on, and exploit our discovery that the extracellular matrix molecule fibrillin-1 regulates TGFbeta bioavailability. We will resolve the molecular basis of how fibrillins regulate TGFbeta, and how we can exploit this knowledge therapeutically. Outcomes will be new insights into how TGFbeta is regulated by the extracellular matrix, and new therapeutic strategies to regulate TGFbeta bioavailability in health and disease.

Technical Summary

Transforming growth factor (TGF)beta is a potent growth factor that regulates cell survival, proliferation, migration and differentiation. Understanding TGFbeta signalling dysregulation in Marfan syndrome and related heritable diseases, and in chronic fibrotic disorders such as sclerosis is a major challenge in the search for effective therapies. We have discovered that fibrillin-1 regulates TGFbeta1 bioavailability by releasing latent TGFbeta from the extracellular matrix. This proposal is to resolve the molecular basis of how fibrillins regulate TGFbeta, and how to exploit this knowledge therapeutically.

Publications

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Chaudhry SS (2007) Fibrillin-1 regulates the bioavailability of TGFbeta1. in The Journal of cell biology

 
Description Wellcome Trust PhD studentship
Amount £100,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 08/2013
 
Title Cell culture models for elastic fibre biology 
Description We have a number of cell culture models to study elastic fibre deposition; they include primary human dermal fibroblasts and the ARPE-19 cell line; we have also developed robust siRNA and shRNA approaches for knockdowns, and retroviral knock-in approaches in these cultures. 
Type Of Material Cell line 
Provided To Others? No  
Impact These cell lines are enabling us (a) to determine the molecular mechanisms underlying elastic fibre formation. 
 
Title Recombinant elastic fibre proteins 
Description We have developed a large panel of recombinant human elastic fibre proteins (including fibrillin-1, fibrillin-2, MAGP-1, fibulins 3-5, LTBPs 1 and 3, periostin). 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact Publications describing molecular interactions in elastic fibre assembly, and structural analyses of a number of these fragments by small-angle X-ray scattering and EM approaches (these structural studies were led by Dr C Baldock). 
 
Description Seminars at European Institutions 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 2007 Lund, Sweden (elastic fibres)
2009 Copenhagen University (elastic fibres)

Collaborative links.
Year(s) Of Engagement Activity 2007,2009