MSTP Associate Director W. Edward Robinson, Jr., M.D., Ph.D.

The research in the laboratory has concentrated on anti-HIV drug development. Working with organic chemists, we are developing new anti-HIV compounds that target a specific viral protein called integrase. Integrase is absolutely required for HIV replication and has no mammalian homolog. Furthermore, integrase is the third of three viral enzymes and the only enzyme for which no inhibitors are used to treat patients. To date, we have identified over 100 compounds that inhibit HIV integrase; some of these are the most potent small molecule inhibitors of HIV integrase yet described. We are using these compounds as tools to better understand the molecular mechanisms involved in HIV integrase function and retroviral integration. In particular we are studying the effects of inhibitor resistance mutations on integrase function and on HIV replication.

 

 

Tallie Z. Baram, M.D., Ph.D.

In the post genomic era, we know that environment and experience shape neuronal function and contribute to human disease. Thus, early-life input, including stress and seizures, may influence the integrity and function of select neuronal circuits and may contribute to the generation of several important neurological diseases such as epilepsy and dementia. Our lab strives to understand the underlying processes in hopes of prevention and intervention.

 

 

Ulrike Luderer, M.D., Ph.D., M.P.H.

Dr Luderer's research is aimed at elucidating the mechanisms by which toxicants disrupt reproductive function and the protective mechanisms that prevent toxicant-induced reproductive dysfunction. Reactive oxygen species are produced during normal ovarian function, and they may also be produced as a result of toxicant metabolism. Our recent work has demonstrated a role for reactive oxygen species in mediating spontaneous apoptosis in follicles deprived of hormonal support and apoptosis caused by exposure to ovarian toxicants. We discovered that reactive oxygen species increased in ovarian follicles cultured without gonadotropin support prior to any increase in endpoints of apoptosis and that follicle stimulating hormone stimulated synthesis of the antioxidant glutathione (GSH) and suppressed the rise in reactive oxygen species (Tsai-Turton and Luderer, 2006). We further showed that GSH depletion in cultured follicles reversed the protective, suppressive effect of follicle stimulating hormone on reactive oxygen species and on apoptosis (Tsai-Turton and Luderer, 2006). This work provides evidence that the protective effects of follicle stimulating hormone are mediated in part via upregulation of GSH synthesis. We also showed that increased generation of reactive oxygen species was an early event in the induction of apoptosis in cultured follicles by dimethylbenzanthracene, a polycyclic aromatic hydrocarbon pollutant (Tsai-Turton et al, 2007a) and in the induction of apoptosis in cultured granulosa cells by the anticancer drug cyclophosphamide (Tsai-Turton et al, 2007b) and by ionizing radiation (Cortes-Wanstreet et al, 2008). Furthermore, depletion of GSH potentiated and supplementation of GSH prevented dimethylbenzanthracene, cyclophosphamide, and radiation-induced apoptosis in follicles and granulosa cells. Together these results demonstrate a critical role for GSH in preventing reactive oxygen species initiated apoptosis in ovarian follicles. Our ongoing work is investigating the interactions between genetic deficiencies in antioxidant capacity and toxicant exposure in ovarian toxicity, reproductive aging and ovarian cancer.

 

Sabee Molloi, Ph.D

Dr. Molloi leads the Imaging Physics Laboratory (http://saturn.radsci.uci.edu/), which focuses on the quantitative aspects of medical x-ray imaging and its applications for cardiovascular disease and breast cancer diagnosis. We are developing new techniques for physiological assessment of coronary artery disease based on angiographic image data. Fractional flow reserve is measured using angiographic images currently used for anatomical assessment of coronary artery stenosis severity. We are also developing new techniques for quantification of breast density using dual energy mammography. Breast density is considered to be an important marker for breast cancer. A breast computed tomography system is also being developed for breast imaging. This new computed tomography system is based on a photon counting detector, which is capable of producing dual energy images without increasing the radiation dose to the patient.

 

Ming Tan, M.D.

Dr. Tan is an Infectious Disease physician who is interested in how bacteria cause disease, with an eye towards developing novel antimicrobial approaches. He is studying Chlamydia as a model system for a chronic bacterial infection. Chlamydial infections are the most common infectious disease reported to the CDC and a major public health problem in both the developed and developing world. Chlamydiae are obligate intracellular parasites, and the main focus of the lab is in defining the mechanisms of chlamydial gene regulation during infection of a eukaryotic host cell. The lab also has a translational project examining the effect of antimicrobial peptides on intracellular chlamydiae.