Research in the laboratory is focused on vascular biology and
how changes in the vasculature can affect heart disease, stroke,
and cancer. The studies correlate microscopy and biochemistry
evidence to determine what changes occur and how these changes
affect the disease process. Currently, three interrelated studies
are ongoing.
In the first, we are trying to learn why in atherosclerosis the
lysosomes of macrophages and smooth muscle cells in the artery wall
become bloated with cholesterol. To do this, we use cultured
macrophages and look at the uptake and processing of cholesterol.
The cholesterol is delivered to the cells within modified
lipoproteins. This is similar to what occurs in vivo. We compare
quantitative microscopic observations on the uptake and fate of the
lipoproteins with measures of key biochemical pathways in
cholesterol metabolism. In this way we are beginning to dissect why
lysosomes cannot clear their cholesterol load. To relate these
tissue culture experiments to the disease process, we also compare
the appearance of these tissue culture cells to that exhibited by
cells during various stages of atherosclerosis. This is also
allowing us to investigate the effect this bloating has on
progression of the disease. Among our findings, we have shown that
lysosomal cholesterol accumulation occurs in two stages. In the
initial stage, cholesteryl esters delivered by lipoproteins are
broken down in th lysosome but the resulting unesterified
cholesterol cannot escape the lysosome. In later stages, and
perhaps related to the free cholesterol accumulation, hydrolysis of
the cholesteryl esters is inhibited. This produces lysosomes rich
in both free and esterified cholesterol.
In the second set of studies, we are exploring how triglycerides
can alter intracellular cholesterol metabolism. We have found that
triglycerides significantly increase the rate of cholesterol
metabolism and cellular clearance of cholesterol. We are now trying
to define the mechanisms by which this occurs.
In a new line of investigation in the laboratory, we are
investigating how inhibition of cholesterol use can effect cell
proliferation. Under conditions where cholesterol is scarce, cell
proliferation, such as that seen in tumors, is slowed. The cell can
acquire cholesterol exogenously or synthesize it internally. Each
pool of cholesterol appears to have a slight different trafficking
mechanism within the cells. It is still not clear whether an
inhibition of use of one pool can be compensated by use of
cholesterol from the other pool. Cholesterol restriction is a
potential means of slowing some tumor growth. However, to fully
understand the potential, much more knowledge of cholesterol
trafficking and utilization within different cell types is
required. . . .
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MeSH terms are retrieved from PubMed records. Learn more.
Key: MeSH Term Keyword
Adult Androstenes Anti-Inflammatory Agents, Non-Steroidal Antibodies, Monoclonal Antineoplastic Agents Apoptosis Atherosclerosis Biochemistry Cancer CD36 Antigens Cell Biology Cholesterol Conserved Sequence Coronary Thrombosis Dimyristoylphosphatidylcholine Endosomes Epithelial Cells Fibrosis Fixatives Heart Hypersensitivity, Delayed Intracellular Traffic Islets of Langerhans Lipid metabolism Magnetic Resonance Spectroscopy Microvilli Mutation, Missense Pathology Phosphatidylethanolamines Precipitin Tests Pressure Protein Interaction Mapping Pyruvic Acid Scattering, Radiation Species Specificity Sphingomyelins Statistics as Topic Thrombin Thrombosis Vacuoles Vascular Biology