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Extracellular regulation of TGFbeta signalling: essential for normal development and dysregulated in disease (e.g. cancer)

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Cell signalling pathways play essential roles in human development and disease. One major signalling pathway, the transforming growth factor (TGF)-β family, plays crucial roles in embryonic development, adult tissue homeostasis and the pathogenesis of a wide-range of diseases from fibrosis to tumour invasion. Therefore, it is critical to understand the different ways in which the TGFβ pathway is regulated, in order that therapeutic strategies can be developed in the future. Research in my lab uses a multi-technique approach to understand the extracellular regulation of growth factors, including TGFβ and bone morphogenetic protein (BMP), which constitute a subclass within the TGFβ family. We know that growth factors are regulated by protein antagonists which bind and inhibit them outside the cell, as well as proteases which liberate the growth factors from inhibitory complexes. A variety of structural, biochemical and biophysical approaches will be used to investigate how these molecules interact and impact upon growth factor function. These findings are directly relevant to understanding growth factor dysregulation in diseases such as Marfan syndrome, cancers and bone disorders. This project offers a unique opportunity to be trained in structural, molecular, and biochemical techniques. Moreover, a structural understanding of how these regulators function will be useful for the development of novel medical strategies and therapeutics.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding. Troilo H, Zuk AV, Tunnicliffe RB, Wohl AP, Berry R, Collins RF, Jowitt TA, Sengle G, Baldock C. Proc Natl Acad Sci U S A. (2014) 111:13063-8.

Fibrillin-1 mutations causing Weill-Marchesani syndrome and acromicric and geleophysic dysplasias disrupt heparan sulfate interactions. Cain SA, McGovern A, Baldwin AK, Baldock C, Kielty CM. PLoS One. (2012) 7:e48634.

Structural and functional evidence for a substrate exclusion mechanism in mammalian tolloid like-1 (TLL-1) proteinase. Berry R, Jowitt TA, Garrigue-Antar L, Kadler KE, Baldock C. FEBS Lett. (2010) 584:657-61.

Role of dimerization and substrate exclusion in the regulation of bone morphogenetic protein-1 and mammalian tolloid. Berry R, Jowitt TA, Ferrand J, Roessle M, Grossmann JG, Canty-Laird EG, Kammerer RA, Kadler KE, Baldock C. Proc Natl Acad Sci U S A. (2009) 106:8561-6.

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