This is a study of human atherosclerotic tissue. We have shown that the cells characterizing such lesion result from a clonal expansion of smooth muscle cells existing in the intima. This study will address the mechanism of this clonal expansion by molecular biologic studies looking for the time course of clonality by characterizing on x-linked heteroallellic marker over the time course of lesion formation. Similarly we will use differential cloning methods to look for markers that distinguish these intimal cells and we will use cultured cells from human lesions to explore possible mechanisms of apoptotic selection. The overall objective of this proposal is to explore the properties that distinguish plaque smooth muscle cells from normal medial smooth muscle. This objective grows out of three simple facts: (1) the intima is defined by the properties of the intimal smooth muscle cell; (2) atherosclerosis is a focal disease of the arterial intima, and (3) the cells of the atherosclerotic lesion comprise a clone.
The Specific Aims are: (1) to determine the time course of monoclonality; (2) to determine whether clonal expansion occurs in vitro; (3) to define intimal-unique genes that mark the plaque smooth muscle cell; (4) to examine the relative role of cell death in expansion of the intima and loss of the media at sites of atherosclerotic progression; and (5) to look for mutations or genetic instability that could confer a proliferative or anti-apoptotic advantage on plaque smooth muscle cells.
