Drug-drug/herb interaction, drug-genetic interaction, signaling of nuclear receptors, transcriptional regulation, and oncogenesis
Based at the University of Rhode Island, our lab is working on the neurotoxicology of environmental agents, with a special emphasis on the developmental basis of Alzheimer’s Disease. Under the direction of Principal Investigator, Dr. Nasser H. Zawia, NL has identified novel drugs for the treatment of AD as well developed diagnostic biomarkers for the disease. Please refer to the Research Interests section for further information.
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.
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?
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?
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?
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