Dr Scott Johnstone

Project title: Connexin 43 as a therapeutic target in cellular proliferation

Cardiovascular disease (CVD) affects over a third of people in developed countries with over 50% of patients being under the age of 60. Blockages within the arteries reduce blood flow to tissues such as the heart and are the greatest contributors to disease. Blood flow can be restored via angioplasty surgeries combined with application of mesh supports called stents onto the blood vessel wall. However, these often fail as a result of smooth muscle cell division.

Our research is focused on understanding why cells divide in an uncontrolled manner in CVD. Previously, we identified that two proteins, connexin 43 and cyclin E, bind each other and initiate smooth muscle cell division and blood vessel blockages.

With the aid of a Carnegie Trust Research Incentive Grant, we tested how these two proteins interact and designed methodologies to disrupt this. Using techniques such as peptide array, we defined regions of protein amino acids unique to connexin 43 in diseased smooth muscle cells and synthesized competing peptides that inhibit smooth muscle cell division.

Our ongoing research is now based at the Robert M. Berne Cardiovascular Research at the University of Virginia (USA). Given the great potential for therapeutic translation, we are working to better understand the underlying protein biology within smooth muscle cells and to create a definitive structure of the protein interacting regions that will be used for future therapeutic design. To this end we have now developed novel techniques to test our peptides for effects in human blood vessels ex vivo.

In addition, we are collaborating with leading researchers in protein structural biology at the University of Virginia, in protein synthesis in cells at Emory University, and in protein interactions and therapeutic approaches at the Virginia Tech Carillion Institute to better understand the roles of these proteins. Using all of these approaches we believe, it may be possible to limit cardiovascular disease associated with cell division in a targeted way.