| | 
yfeng@usuhs.mil
M.D., Wuhan University, China, 1983
Ph.D., University of Oxford, 1993
Structure-function relationship, signaling mechanism, and translational research of G-protein-coupled receptors
Current Program
Molecular mechanisms of G protein-coupled Angiotensin II receptor AT1 and AT2 in ligand recognition, conformational activation, signal transduction, nuclear translocation, desensitization, and internalization
Deorphanization of G protein-coupled orphan receptors.
Pharmacoproteomics.
Brief Description:
G-protein coupled receptors (GPCRs) represent the primary mechanism by which cells sense alterations in their external environment and convey that information to the cells’ interior. Abnormalities of delicate signaling mediated by this mechanism are often attributed to diseases and disorders, e.g. hypertension, preeclampsia, hypertrophy, cancer, fibrosis, diabetes, and human CNS diseases. Thus, study of mechanistic and functional properties of these GPCRs will help understand the pathogenesis of many diseases.
Intervention at the level of GPCRs has a proven history of being excellent therapeutic targets. More than 50% of drugs on market target this superfamily of receptors with known native ligands. The current total market for GPCR drugs such as antihistamines, AT1 antagonists, and beta-blockers is $60 billion. Out of 800 human GPCRs identified by human genome projects, more than 600 remain orphan receptors for which the native ligands are unknown. With current techniques available, identifying the native ligand (deorphanization) requires about 5 years and costs millions of dollars per receptor. This has become an apparent bottleneck for drug discovery that targets GPCRs. It also hampers biomedical advance on many fronts. Thus, study of mechanistic and functional properties of these GPCRs will expedite drug discovery and open up new avenues for biomedical research, i.e. cancer, diabetes, CNS disease, and cardiovascular diseases. This represents a major challenge in functional genomics.
Differences in structure-function and signal transduction of subtype receptors represent another major challenge to understand the role of GPCRs in nature and biomedicine. Elucidation of these differences and their mechanisms will greatly advance receptor biology, pharmacology and therapeutics.
G protein-coupled Angiotensin II receptors are associated with hypertension, preeclampsia, cardiac hypertrophy, renal fibrosis, and diabetes. These receptors are the model system that is studied in our laboratory for understanding ligand recognition, agonist-induced activation, constitutive activation, inverse agonism, internalization, G protein coupling, EGF receptor transactivation, and AT2-mediated inhibitory signaling. This is the first major area of our research.
The second major area is deorphanization. This laboratory has cloned more than 30 orphan GPCRs. In-house technology detecting receptor activation is developed and applied for deorphanization of these receptors.
The third major area is in pharmacoproteomics. Pharmacoproteomic analysis of AT1 antagonists is a new research program developed in our laboratory. This program will lead to broader understanding of drug actions.
In addition, we collaborate with Dr. Gorodeski at Case Western Reserve University and has identified a novel P2X7 isoform. Our laboratory is working on signal transduction of the novel isoform and the potential pathological role in Alzheimer disease.
State-of-the-art techniques in molecular biology, genetics, cell biology, biochemistry, molecular pharmacology, and bioinformatics are used for these studies. These techniques including proprietary reporter system to monitor Ca2+, various GST, GFP fusion proteins and epitope-tagged proteins, mutagenesis, bioluminescence resonance energy transfer (BRET), Fluorescence RET, confocal microscopy, bioinformatics, DNA Microarray, proprietary assay of receptor internalization, in-house vector system for high-level mammalian overexpression of proteins, molecular modeling, peptide binding, in vitro translation, gene cloning, two-hybrid system, ChIP, proteomics, and laser capture microdissection. They are used together with many routine biochemical and pharmacological technologies.
Pubmed Search
| |
