Montclair State Digital Montclair State University Digital Characterization of a c-Jun N-Terminal Kinase Pathway in the Characterization of a c-Jun N-Terminal Kinase Pathway in the Parasitic Nematode, Brugia malayi Parasitic Nematode, Brugia malayi

Lymphatic filariasis (elephantiasis) is a major neglected disease caused by filarial nematodes including; Wuchereria bancrofti, Brugia malayi {B. malayi) and Brugia timori. Over 120 million individuals are infected and more than 1.3 billion people are at risk of infection in 81 endemic countries. Current treatments are limited, toxic and fail to kill adult parasites. There is a need for new target and treatments. One potential novel drug target for this disease is stress-activated protein kinases. It has been previously demonstrated in our laboratory that a B. malayi stress-activated protein kinase, Bm-MPK1, an ortholog of the human p38/Caenorhabditis elegans (C. elegans ) PMK-1, plays a role in protecting B. malayi from oxidative stress. I have characterized a second, evolutionary conserved stress activated kinase pathway, the c-Jun N-terminal kinase (JNK) pathway. B. malayi expresses a single JNK kinase (Bm-JNKl) isoform which is highly homologous to both human and Caenorhabditis elegans (C. elegans) JNK kinases. In C. elegans, it has been demonstrated through genetic means that JNK plays a role in several responses such as heavy metal stress, heat shock, and coordination of movement. Using heavy metal stress as a model system, I have demonstrated that treatment of B. malayi parasites with human JNK inhibitors, under heavy metal stress conditions, results in decreased motility and viability of adult and larval forms of the parasite. Furthermore, I have expressed recombinant Bm-JNKl and characterized its enzymatic activity with the ultimate goal of screening JNK inhibitors for activity against this enzyme. These results define a JNK pathway in B. malayi with functions similar to those found in C. elegans.