application): Blood vessels are lined with a thin layer of specialized cells called endothelium that forms a critical barrier controlling the exchange of circulating blood molecules, nutrients, cells and even drugs from the blood to the internal compartments and cells of the tissue. This exchange defines the molecular permeability of small blood vessels called microvessels or capillaries and is critical for the normal growth, maintenance and survival of all tissues of the body. Abnormal exchange contributes to organ dysfunction, tissue cell death, and the pathogenesis of many cardiovascular diseases such as atherosclerosis and complications of diabetes. The broad focus of this project is to define the molecular and cellular basis of the barriers and pathways that mediate capillary permeability. The ability of the endothelium to act both as a restrictive barrier to transvascular exchange and as a specific receptor-mediated translocator of molecules is dependent on cell surface population of distinct vesicles called caveolae which may play an important role in the transport of select macromolecules into and across the endothelial cell barrier. The molecular structure and function of caveolae will be investigated by using novel technologies and transport assays developed in the lab. Because albumin is the major protein in blood and acts as a carrier for many important nutrients, we will examine its interactions with the endothelium. Albumin can increase the restrictiveness of the endothelial cell barrier while conversely facilitating the transendothelial transport of select molecules such as fatty acids and even drugs. The mechanisms mediating these effects are uncertain. The investigator's work discovered that albumin interacts with endothelium and traverses it by binding to a specific receptor called albondin (gp60), which is concentrated in caveolae that can bud from the cell surface to form free transport vesicles. Specific albumin binding domains in albondin will be determined. Small molecules will be created to inhibit albumin binding and transport. The mechanisms by which caveolae transport their molecular cargo via the distinct steps of budding, docking and fusion will be examined at the molecular level. Because mutations in specific caveolar proteins inhibit transport, the investigators will study how these proteins function in caveolar transport. Their quest for basic knowledge at the molecular level about the function of caveolae and vascular endothelium in transport has elucidated novel targeting strategies that are potentially useful in achieving tissue-specific drug and gene delivery for the treatment of many diseases.
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