My laboratory is interested in redox regulation of gene expression with an emphasis on selenium and its role in immune regulation.
Respiratory burst and the reactions of the electron transport system in mitochondria have the ability to produce a variety of oxygen and nitrogen radicals, commonly called reactive oxygen or nitrogen (RONS) species by different mechanisms. Although these RONS play an important role in the defense of the host, increased production of these radicals is thought to be one of the major mechanisms accompanying inflammation, as seen in atherosclerosis, cancer, asthma, Alzheimer's disease and arthritis. Many epidemiological studies have suggested a link between increased oxidative stress and exacerbated HIV-1 replication. It is increasingly recognized that many cellular signaling pathways are oxidation-sensitive, and that ROS may provide a common link between proinflammatory pathways and pathologies. Extensive evidence from many laboratories, including ours, indicates that ROS can regulate gene expression by modulating a large number of redox-sensitive transcription factors. Therefore, the antioxidant capacity of immune cells (e.g., macrophages) is very important to maintain optimal overall redox or oxidative tone. This is accomplished by a multi-tier system in which selenium (Se) in the form of Se-glutathione peroxidases, thioredoxin reductases, and other selenoproteins. Selenium is an essential micronutrient that functions mainly through ~25 selenoproteins. Deficiency of Se is known to be fatal. Selenium deficiencies are commonly seen in to occur in individuals with chronic renal failure, malnutrition, malabsorption, long term parenteral nutrition, chronic infections, and HIV/AIDS. Several epidemiological studies suggest that Se-supplementation to HIV-seropositive individuals decrease oxidative stress and help in boosting the immune response. However, the exact mechanism of antioxidant and anti-inflammatory properties of Se is still unclear.
Recently, we have discovered a novel mechanism where selenoprotein(s) plays a pivotal role in shunting the arachidonic acid towards an anti-inflammatory prostaglandin (15-deoxy-delta12,14-PGJ2) rather than pro-inflammatory PGE2 or thromboxane B2 (TXB2). The implications of this “switch” seem to be important in catabasis or resolution of inflammation. In addition, 15d-PGJ2 being a Michael acceptor electrophile, can interact covalently with many protein free thiols and modulate their function. We are currently examining how might selenoproteins bring about this switch. Studies are also focused on the regulation of several PG synthases, at the transcriptional level, to understand the existence of feed back loops that ultimately lead to the switch in the production of PGs (See Current Projects). While the studies described above seek to elucidate the basic antioxidant and anti-inflammatory properties of Se, the outcomes of these projects will be translated to develop novel therapeutics in four projects (See Current Projects):
- Regulation of HIV-1 transcription by Se and the role of 15d-PGJ2 in HIV transcription and replication (in collaboration with Dr. Andrew Henderson at Center for AIDS Care and Research, Boston University College of Medicine)
- Novel synthetic derivatives of organo-Se compounds and their role in inflammation in melanoma (studies performed with Drs. Shantu Amin, Dhimant Desai, and Gavin Robertson at the Penn State College of Medicine at Hershey)
- Breast cancer metastasis to the bone (with Dr. Andrea Mastro, Biochemistry and Molecular Biology, Penn State )
- Isolation and characterization of endogenous bioactive compounds as immune modulators.
A second project is on the elucidation of the physiological role of myo-inositol oxygenase, a unique monooxygenase expressed in the proximal tubular cells of the kidney cortex, retinal and lens epithelial cells, and sciatic nerve. MIOX was first purified by Dr. C. Channa Reddy, my post-doctoral mentor about 20 years ago. myo-Inositol (MI), the dominant form of the physiological inositol isomers, is utilized in many tissues and cell types as an organic osmolytes and, more importantly, as a precursor for the synthesis of phosphoinositide second messengers. The first committed step in MI catabolism is catalyzed by a poorly studied enzyme called MI oxygenase (MIOX; EC 184.108.40.206). We are interested in understanding several aspects related to the enzymology of MIOX (in collaboration with Dr. Martin Bollinger, Associate Professor of Chemistry and Biochemistry and Molecular Biology, at Penn State ), protein-protein interactions, transcriptional regulation by hyperosmotic and hyperglycemic stress (See Current Projects).
If you have any questions or if you are interested in the current line of investigation, please contact Dr. Sandeep Prabhu.