Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality worldwide. Current treatments for atherosclerosis focus on prevention or vessel repair with very few targeting the cellular events leading to the progression of atherosclerosis. At the cellular level, the main effector cell of atherosclerosis is the foam cell which is formed when macrophages undergo a morphological change associated with engulfment of lipids. This is facilitated by the cytoskeleton which plays important roles in cell shape and function. Important components of the cytoskeleton are the tubular polymers formed by the polymerization of dimers of ?- and ?- tubulin called microtubules. The stability, dynamic properties, and behavior of a microtubule depend on the composition of ?-tubulin isotypes, of which there are many. The expression of these individual ?-tubulin isotypes can differ greatly across cell or tissue type. We hypothesize that a specific subset of ?-tubulin isotypes regulates foam cell formation and function. To understand the role of ?-tubulin isotypes in foam cell formation and function, we propose a comprehensive approach integrating in vitro and animal models to gain an understanding of the biologically relevant roles ?-tubulin isotypes play in foam cell formation and the development of atherosclerotic plaques.
We aim to establish the expression, distribution, and role of individual ?-tubulins during foam cell formation in vitro using primary cells (bone-marrow derived macrophage) and to determine the mechanism of ?- tubulin-dependent foam cell formation in vivo using mouse models of atherosclerosis. ?-tubulin isotype levels and cellular distribution will be measured in primary cells undergoing foam cell formation and within aortic lesions using ?-tubulin isotype-specific antibodies. ?-tubulin gene expression will be quantified in cells and aortic tissue using qRT-PCR. In addition, the effect that altering individual ?-tubulin isotypes in primary cells or, with ?-tubulin binding drugs in mice, has on foam cells will be assessed. The proposed study will define the specific ?-tubulin isotypes involved in foam cell formation. Knowledge that we will gain could be used to design specific drugs that inhibit foam cell formation, and subsequent plaque formation, by targeting specific ?-tubulin isotypes.
Atherosclerosis is a major health problem responsible for a number of diseases including ischemic heart disease, heart attack, stroke and the majority of deaths globally. The basis of this proposal is to determine the roles specific ?-tubulin isotypes play in foam cells, the main effector cells of atherosclerosis that are responsible for plaque development. The identification of a specific ?-tubulin isotype important in foam cell formation or function would be a first step in the long-term development of ?-tubulin isotype-targeted drugs that would inhibit foam cell formation, block the progression of atherosclerosis, and revolutionize how this disease is treated.
