Head – Alex Bobik
Research in the Vascular Biology & Atherosclerosis focuses predominantly on atherosclerosis and its regulation by cytokines and immune cells. Atherosclerosis is a disease of medium to large arteries that is the major cause of heart attacks and strokes. It is the consequence of excess lipid accumulation in vessels, which triggers an immune response, and the secretion of inflammatory cytokines that promote its development.
This lab pursues three main areas of research:
-
Cellular and molecular mechanisms that promote atherosclerosis (inflamed fatty lesions that develop in blood vessels and cause strokes and heart attacks)
-
Mechanisms that lead to development of cardiac fibrosis (where excessive collagen stiffens the heart muscle and impedes electrical conduction leading frequently to sudden death)
-
Understanding how bone marrow-derived stem cells can be used to repair the heart after damage from a heart attack.
During 2005 Alex was able to show that a specific cell type of the immune system called a regulatory T cell is important in controlling the development of atherosclerosis. These cells, which can be identified by the expression of specific markers on their cell surface called CD4 and CD25, were shown to reduce the development of atherosclerosis in genetically modified mice. When these cells are removed mice develop more severe atherosclerosis. These studies have important implications for the treatment of atherosclerosis and have the potential to be used in conjunction with other therapies to prevent development of severe lesions. This is currently being studied.
Other cell types are also being studied, in particular cells that cause inflammation and promote the development of atherosclerotic lesions that are rich in fat and low in collagen. These lesions are weak and highly susceptible to rupture, which can cause a blood clot and lead to strokes and heart attacks. These include immune cells called natural killer T cells (NKT) cells. Alex and his team have shown that a specific type of NKT cell, which can be identified by expression of the marker CD4, promotes development of these lesions. Research is continuing into how they do this.
Other studies on atherosclerosis focus on proteins that are secreted by macrophages, cells in the body’s circulation that accumulate in lesions and take up fats. One such protein called high mobility group box protein-1 appears to be a potent stimulator of atherosclerosis.
Studies on cardiac fibrosis have led to the identification of unexpected mechanisms that promote fibrosis. When the heart has to pump against high pressure, such as in hypertension, the heart muscle produces proteins that attract specific bone marrow derived cells from the circulation. Alex and his team have identified two such proteins called secondary lymphoid chemokine and monocyte chemotactic protein-1. These attract several circulating cell types into regions of developing fibrosis including lymphocytes that express the marker CD4, macrophages, and an as yet unidentified cell that produces large amounts of collagen. Current studies are focused on depleting these cell types in mice and examining how this affects the development of fibrosis and proteins that regulate collagen production, in particular transforming growth factor-beta and interleukin-10.
Studies on the role of bone marrow derived cells in healing the heart after a heart attack have shown that a substance which Alex’s lab has shown improves healing, called granulocyte-colony stimulating factor (G-CSF), increases the number of blood vessels in the damaged region. It does this by stimulating the production of growth factor systems that promote the development and growth of new blood vessels. These include vascular endothelial cell growth factor-A, placental growth factor and thymidine phosphorylase. This lab is currently studying bone marrow-derived cells that invade the damaged region and their contribution to development of new blood vessels producing these.
Another area of study is the possibility of using genetically modified bone marrow stem cells to attract heart stem cells into damaged regions of the heart to further improve cardiac repair.