The
group's research, built on a foundation of physical and synthetic
organic chemistry, bridges chemistry, biology, and medicine.
Previous accomplishments and continuing interest focus on the biologically
important chemistry of lipids.
- Discovery of naturally occurring molecules
and their biologically important chemistry guided by prior total synthesis
of targets identified by mechanistic considerations
- This unconventional approach was
especially effective for the discoveries of levuglandins
and isolevuglandins, oxidized
lipids that are so extraordinarily reactive that isolating them
from biological sources has not been possible.
- Mechanistic elucidation of lipid oxidative
pathways and the reactions of oxidized lipids with biological nucleophiles
such as proteins and DNA
- The reactions of oxidized lipids,
such as levuglandins, with proteins
and DNA are often toxic events that may contribute to disease processes.
- Investigation of the influences of
biological environments such as membranes and lipoprotein
particles, on lipid oxidation and the chemistry of oxidized lipids
- Compartmentalization and the lipophilic-hydrophilic
dichotomy are pervasive characteristics of biological systems.
- Detection and structural characterization
of disease-related lipid-based oxidative modifications of proteins
with immunological, mass spectroscopic, and chromatographic tools
- The exquisite sensitivity and structural
selectivity of antibodies are well-suited for detecting posttranslational
lipid-based modifications of proteins in biological systems, such
as retina.
- Mass spectroscopic techniques provide
an abundance of structural information that allows microscale characterization
of the protein targets of lipid-based oxidative modification.
- Clinical investigation of the involvement
of lipid oxidation in disease, such as atherosclerosis
- Protein adducts of certain lipid
oxidation products, e. g., isolevuglandins,
provide a dosimeter for oxidative stress that is more closely
correlated with cardiovascular disease than are classical risk
factors, e. g., total serum
cholesterol or LDL cholesterol levels.
- Protein-bound carboxyethylpyrroles
are docosahexaenoate-derived oxidative modifications that are
grossly elevated in the retinas of individuals with age-related
macular degeneration.
- Design, synthesis, and evaluation
of new medicinal agents
- Lipophilic histidine-containing
nucleophiles that intercept and detoxify electrophilic lipid oxidation
products are potentially useful competitive inhibitors of lipid-based
oxidative protein modification. Such an antielectrophile defense
may complement the well-known antioxidant defenses.
- Lipophilic analogues are potentially
useful inhibitors of receptor-mediated, e.g., CD-36, cellular
resopnses to certain oxidized phospholipids.
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