Project Summary/Abstract
Chemokines are a family of small cytokines best known for their ability to guide directed migration of cells
expressing corresponding chemokine receptors. In addition to their activities in recruiting leukocytes for
inflammatory reactions, emerging evidence has revealed that chemokines can also modulate the activities of
many non-immune cells, such as endothelial cells, fibroblast, adipocytes, and tumor cells, among others, by
binding to chemokine receptors expressed on these cells. The C-C Motif Chemokine Ligand 2 (CCL2, also
known as monocyte chemoattractant protein-1, MCP-1) and its main receptor CCR2, a G protein-coupled
receptor, have been receiving particular interest for their involvement in the pathogenesis of many diseases,
including neurological diseases, atherosclerosis, obesity, diabetes, and various types of cancer. However, the
intracellular mediators of CCL2-CCR2 signaling are largely unknown. Moreover, although blocking CCL2-
CCR2 axis was found to be effective in several preclinical disease models, clinical trial studies of these
inhibitors have shown a lack of effect, likely due to developed compensation by other chemokines and/or
chemokine receptors for the loss of function of CCL2-CCR2 axis. However, the compensatory chemokines/
chemokine receptors for CCL2-CCR2 axis have been poorly defined. It is our goal for next five years to
elucidate the intracellular mediators of CCL2-CCR2 signaling as well as the compensatory machinery for this
axis in prostate cancer models particular under obese condition. Another area of research in my laboratory is
the discovery of bioactive natural compounds. Natural compounds particularly phytochemicals are a major
source for developing non-toxic preventive/therapeutic agents. Phytochemicals typically target multiple
dysregulated signaling pathways involved in the development of polygenic diseases such as cancer, obesity
and diabetes, therefore they may be able to provide a durable control of these diseases. However, the low
bioavailability of most phytochemicals limits their efficacy in humans, and their effective doses as observed in
vitro can barely be achieved in vivo. Discovery of highly effective phytochemicals with favorable bioavailability
is therefore an urgent task of global priority in disease control. In our preliminary study we have identified that
arctigenin, a novel anti-inflammatory lignan mainly from the herb Arctium lappa, was a potent inhibitor of
various types of cancer cells with a potentially favorable bioavailability. Arctigenin has also shown to be anti -
oxidant, -viral, -obesity, -diabetes, -osteoporosis, -cardiovascular diseases, -neurological diseases, and
immune modulatory. Our next five years’ goal in this line of research is to fully characterize arctigenin in terms
of its direct and indirect molecular targets, pharmacokinetics, and its potential influence on drug-metabolizing
enzymes. The overall vision of my research program is to provide essential scientific knowledge and agents to
improve the prevention and treatment of certain chronic disease including obesity and cancer, and to improve
the quality of life of patients and their families.