I-204C Health Sciences
Dr. Furlong's laboratory is investigating the functional genomics of the polymorphic, HDL-associated enzyme human serum paraoxonase (PON1). The main known physiological function of this protein is to metabolize toxic oxidized lipids and protect against vascular disease.In addition to this role, PON1 is also important in detoxifying organophosphorus Insecticides such as chlorpyrifos and diazinon are bioactivated to highly toxic oxon forms by the cytochrome P450 systems. The toxic oxons are potent inhibitors of acetylcholinesterase. These oxons are hydrolyzed by PON1. Direct testing of PON1's protective effects against organophosphate poisoning (OP) in a mouse model system verifies the role of PON1 in detoxication in vivo. PON1 exhibits a substrate-dependent polymorphism in human populations. At least two allelic forms of the enzyme have been observed. One alloform (PON1R192) hydrolyzes chlorpyrifos oxon (the toxic metabolite of chlorpyrifos or Dursban®) with a high catalytic efficiency and the other (PON1Q192) with a lower catalytic efficiency. Both PON1 alloforms detoxify diazoxon (the active metabolite of diazinon) with equal efficiency.
As noted above, PON1 appears to play an important role in metabolizing toxic oxidized lipids. A number of recent studies have reported that the R192 variant of this protein is a risk factor for coronary artery disease. Our own studies carried out in collaboration with Dr. Gail Jarvik have shown that low PON1 levels are a risk factor for carotid artery disease. The functions of two related proteins, PON2 and PON3 are also being investigated. Rates of phenyl acetate and paraoxon are differentially affected in both vascular disease and Parkinson's disease (PD). Measurement of the ratio of substrate hydrolysis detects 40% of males with PD, but not females. This apparent difference is attributable to higher levels of the antioxidant protein PON2 in the mitochondria of females. Neurons from female mice are much more resistant to oxidative stress than neurons from male mice, however, this difference is not observed in female PON2 knockout mice. Recombinant PON1 is protective against OP exposures.
A second interest of Dr. Furlong's laboratory is the development of surface plasmon resonance (SPR) biosensors that have a broad range of applications in the fields of medicine, biotechnology and environmental monitoring. For monitoring applications, the sensors are capable of detecting small molecules such as hormones, insecticides, nerve agents as well as larger analytes including toxic proteins, viruses and microbes. As general laboratory instruments, the SPR biosensor systems are capable of monitoring in real time, biomolecular interactions such as the interaction of transcription factors with specific DNA sequences, interactions of protein subunits with complexes and receptor/ligand interactions.
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Fred Hutch | University of Washington
Institute for Systems Biology (ISB)| Center for Infectious Disease Research