Date of Award
Master of Science (MS)
College of Science and Mathematics
Chemistry and Biochemistry
Thesis Sponsor/Dissertation Chair/Project Chair
Lymphatic filariasis (elephantitis) is a disfiguring disease caused by thread-like nematodes. This disease affects the lives of over 120 million people and over one billion people are at risk for infection in endemic regions. Drugs used to treat this disease suffer from toxicity and emerging resistance and new therapies need to be identified. Our laboratory has been studying the filarial parasite, Brugia malayi (B. malayi), one of the causative agents of this disease. The laboratory is focused on the study of critical protein kinase signaling pathways, necessary for parasite protective anti-oxidative responses, as potential therapeutic targets. We have previously determined, using a bioinformatic and chemical biological approach that the B. malayi stress-activated protein kinase, Bm- MPK1, plays a critical role in defense against reactive oxygen species (ROS) stress generated by the innate immune system. The first part of my thesis extends our previous observation by examining the role of Bm-MPKl in protection against reactive nitrogen „ species (RNS) which are also generated by the innate immune system during infection. I have found that treatment of the adult parasites with the Bm-MPKl inhibitor, BIRB796, in the presence of RNS, leads to a reduction in parasite viability. These results implicate Bm-MPKl in a protective signaling pathway against both ROS and RNS.
The second part of my thesis explores the generality of the use of bioinformatics, comparative genomics and chemical biological approaches for the identification of potential parasitic protein kinase targets. Using genomic data for the nematode Caenorhabditis elegans (C.elegans) and B. malayi, I have identified B. malayi Src kinase as a potential drug target. Treatment of adult B. malayi parasites with the clinically approved human Src inhibitor dasatinib (Sprycel®), leads to decreased viability and defects in embryogenesis similar to those seen in C. elegans Src genetic knockdowns.
De Martini, William R., "Combining Bioinformatics and Chemical Biological Approaches to the Study of Signaling Pathways in Parasitic Nematodes" (2011). Theses, Dissertations and Culminating Projects. 814.