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Mechanisms of neovascularisation: the role of the cytoskeleton in angiogenesis

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

About This PhD Project

Project Description

Angiogenesis is the fundamental physiological process by which new blood vessels are generated from pre-existing vasculature. It plays a critical role in elaboration of the vasculature during development; however, this process is also triggered in hypoxic tissue in the adult organism – for example, in response to myocardial infarction or stroke. This neovascularisation plays an important role in healing and regeneration. In addition to its positive roles in tissue healing, angiogenesis is also triggered in several disease states. In cancer, solid tumors secrete angiogenic factors that force the body to create a new blood supply for the tumor, supporting its growth and metastasis. Because of the importance of angiogenesis in health and disease, major efforts have been focused on understanding the processes that control it. Understanding the mechanisms of angiogenesis is critical for the development of new drugs for the clinical control of blood vessel formation.

Angiogenesis requires that the endothelial cells of quiescent vessels undergo a profound set of changes. In response to pro-angiogenic signals, cells invade through the basement lamina into the surrounding tissue and begin to proliferate. The invasive cells become highly-elongated and organize into cord-like structures that migrate collectively towards the source of pro-angiogenic signals. These endothelial cell cords then become tubes by forming a central lumen, allowing them to accept blood flow and to become functional vasculature. In angiogenesis, cells must undergo dramatic changes to their shape. We currently know very little about the mechanisms controlling this, but it must involve regulation of the cytoskeleton, which gives shape and movement to all cells.

We have used siRNA screening of assays of angiogenesis to identify novel cytoskeletal regulators of blood vessel formation. The aim of the project is to understand how these new proteins work and to determine their roles in the angiogenic process. The project will involve high-resolution imaging of endothelial cells, using both fixed cells and live-cell imaging. We will use proteomic approaches to map the novel cytoskeletal signalling pathways and a range of assays of angiogenesis to discover how shape change is controlled during the formation of new blood vessels. The project has direct relevance to the treatment of cancer and vascular disease.

Webpages:
http://www.bris.ac.uk/biochemistry/people/harry-h-mellor/overview.html

References

Richards M, Hetheridge C and Mellor H (2015) The formin FMNL3 controls early apical specification in endothelial cells by regulating the polarized trafficking of podocalyxin. Curr. Biol. [Epub ahead of printing] doi: 10.1016/j.cub.2015.07.045

Hetheridge C, Scott AN, Swain RK, Copeland JW, Higgs HH, Bicknell R and Mellor H. (2012) The novel formin FMNL3 is a cytoskeletal regulator of angiogenesis. J Cell Sci. 125, 1420-1428.

Potente M, Gerhardt H, Carmeliet P. (2011) Basic and therapeutic aspects of angiogenesis. Cell 16, 873-87.

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