Dinesh Thotala, PhD

Washington University in St. Louis (WU)

My research interests in experimental therapeutics focus on improving radio therapeutic treatment regimens. Two specific research areas are increasing the radioprotection of normal neuronal cells and enhancing radiation responses of vascular endothelium. Ionizing radiation induces activation of PI3K/Akt pathway, which is highly involved in regulation of endothelial cell viability during radiotherapy. Inhibition of this signaling pathway enhances the cytotoxic effects of radiation in tumor vascular endothelium resulting in enhanced tumor control. I study the molecular mechanism of radiation induced activation of PI3K/Akt signaling, aiming to discover novel therapeutic targets for enhanced radiotherapy. Activation of the protein kinase GSK-3ß has been shown to inhibit a number of critical transcription factors involved in promoting cell survival and proliferation. My work has shown that inhibiting radiation-induced GSK-3b activity and its down-stream targets (ß -catenin and cyclin D1 functions) will selectively protect hippocampal neurons from radiation-induced damage, leading to increased survival of normal tissue compared to tumor cells. Further, small molecule inhibitors of GSK-3ß prevent radiation induced cell death by reducing apoptosis in the stem cells of the GI epithelium, improving survival of the mice. The mechanisms of radioprotection by GSK-3ß inhibitors could involve regulation of MDM2-dependent p53 accumulation and interactions between GSK-3ß, MDM2 and p53. The experience and the insights that I have gained in various aspects of cell biology, radiation biology and molecular biology enable me to apply my knowledge to address the questions in cancer research, now having an opportunity to use imaging tools like MRI and PET for screening and validating drugs and drug targets.