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The primary focus of
my research is on the understanding of how genetic and environmental
factors coordinately regulate the expression of genes involved in drug
response and oncogenic switch. More specifically, the research
activities are designed to answer such questions as: how does genetic
or environmental factor contributes to differences in drug-response?
How does transcriptional regulation switch from physiological (e.g.,
drug-metabolism) to pathological response (oncogenesis)? And how do
drugs, hormones and herbs alter respective therapeutic activity when
used together? Currently, there are four ongoing projects, and these
projects are closely related through sharing functionality or
regulatory mechanisms.
Project
1. Molecular Toxicology of Carboxylesterases
Carboxylesterases
represent a class of hydrolytic enzymes and have two major functions:
(1) they hydrolyze drugs such as aspirin, tamiflu and irinotecan as
well as endogenous compounds such as cholesterol esters and
triglycerides; and (2) they detoxify pesticides such as
organo¬phosphates. This project focuses on four aspects:
(a) How do
carboxylesterases recognize substrates or inhibitors with dissimilar
structure
(b) To which extent
does genetic variation alter hydrolytic metabolism of drugs.
(c) Is the expression
of carboxylesterases altered by drugs, herbs and hormones?
(d) What are the
critical steps involved in the biosynthesis, tissue distribution and
cellular trafficking of carboxylesterases?
Project 2. Signaling of the Pregnane X receptor (PXR)
The pregnane X
receptor is a master regulator on the expression of genes involved in
drug-metabolism and lipid homeostasis (e.g., cholesterol). This
receptor has two functional domains to mediate DNA binding and ligand
interaction, respectively. In contrast to other nuclear receptors, the
pregnane X receptor shows profound promiscuous properties on both DNA
and ligand binding. This project focuses on four aspects:
(a) How does PXR
exert selective DNA binding in the genome?
(b) What are the
major players in PXR-directed transcriptional complex?
(c) Is the activity
of PXR altered by pathological conditions such as inflammation?
(d) How do genetic
variants of PXR alter drug-metabolism?
Project 3. Functional Characterization of DEC1 Transcription Factor
DEC proteins
constitute a new and structurally distinct class of bHLH proteins and
are involved in various cellular events such as cell differentiation
and apoptosis, regulation of molecular clock, and acute-phase
response. This project focuses on four aspects:
(a) What is the
biological significance of cytokine-induced expression of DEC1?
(b) How does DEC1
exert antiapoptotic activity?
(c) Is DEC1 involved
in cell transformation?
(d) Does circadian
expression of DEC1 contribute to drug-resistance?
Project 4. Herb-Drug
Interaction
Herbal supplements
are widely used for cosmetics, energy enhancement, disease prevention
and treatment. As many as 80% of the world’s population use some forms
of herbal medicines as part of their primary health care.
n the United States,
the use of herbs has skyrocketed in the past several years, and the
sales are growing by more than 20% annually. Herbal medicines and the
use of these agents are featured by multiple active constituents,
metabolism-mediated toxicity and co-administration with pharmaceutical
drugs. Combined use of herbs and drugs may have profound clinical
consequences so called herb-herb or herb-drug interactions. Many
interactions in these natures are due to the altered metabolism or
modulation on the activities of several major nuclear receptors
including the peroxisome proliferator activated receptors (PPAR), the
liver X receptors (LXR), the farnesoid X receptor (FXR) and the
pregnane X receptor (PXR). This project focuses on several major
herbal remedies such as St John’s wort, gugglipid. We are currently
working on two aspects:
(a) To determine
whether active components in these remedies undergo metabolism
(b) To determine
whether the metabolites (if there are) are biologically active toward
the aforementioned receptors
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