Schistosomiasis is a neglected tropical disease that infects nearly 200 million people a year in various portions of the world. Today, there is only one known drug treatment: praziquantel. Our goal is to identify alternative therapies that may be used in the event of praziquantel resistance. Nicotinic acetylcholine receptors (nAchRs) are known targets for drugs that treat other parasitic infections, and so they are a logical place to search for new schistosomiasis therapies. My project is to identify these acetylcholine receptors from the parasitic worm Schistosoma mansoni, and clone them as a first step to studying them in the lab. I have done this using polymerase chain reaction (PCR) and molecular cloning techniques. With successful results, the next step is to inject the DNA sequence for our receptors into worms lacking nAchRs and determine whether they are functional. Functional clones will resolve the mutation and eliminate the paralysis. With this confirmation, we can move forward with anti-parasitic drug screening targeting these receptors.

Alzheimer’s disease (AD) accounts for one sixth of all deaths in the United States, as well as a fifth of deaths for those 65 and older. It is a neurodegenerative disease characterized by the accumulation of beta-amyloid, a post-cleavage product of amyloid precursor protein (APP), leading to the creation of reactive oxygen species (ROS) that promote mitochondrial degradation, a problem also found in Parkinson’s disease (PD) models. In AD models, the fission protein dynamin related protein-1 (Drp-1), found on the outer mitochondrial membrane (OMM), is overactivated, thus leading to the constant breakdown of mitochondria and eventual neuronal death. We can combat this overactivation through utilizing the enzyme protein kinase-A (PKA), which is pulled to the OMM by the scaffolding protein dual specificity A-kinase anchor protein-121 (AKAP121), also found on the OMM. Once on the OMM, PKA works to inhibit the activity of Drp-1, thus alleviating mitochondrial degradation in AD models. My project will focus on two major facets of the AKAP121/PKA/Drp-1 relationship through: 1) testing pharmacological compounds on their ability to increase the level of endogenous AKAP121 in the OMM , and 2) determining whether modulating the level of PTEN-induced kinase 1 (PINK-1), which increases binding between D-AKAP121 and protein kinase A in the mitochondrion, will increase mitochondrial efficiency. By filling this knowledge gap, we draw closer to an eventual therapeutic drug that activates PKA as a source of protection against mitochondrial degradation in the brains of humans affected by AD.

Schistosomiasis is a neglected tropical disease that is caused by parasitic flatworms. This is usually found in third world countries such as the Middle East, South America, Southeast Asia, and sub-Saharan African affecting over 200 million people a year. Schistosomes reside in fresh water and penetrate the skin of their host when people urinate or defecate near fresh bodies of water or swim, wash, or clean in that water. The only clinical treatment available is Praziquantel (PZQ), which only targets adult worms and not juvenile larval stages. This raises the concern of emerging drug resistance and reinfection, which makes finding a new treatment to combat the high infection rates so much more important. We are looking at finding a new treatment that can be used instead of PZQ that will target schistosome neurotransmitter receptors which control muscle contractions. G-protein coupled receptors are the largest known superfamily of transmembrane receptors that play a role in biological processes like growth, differentiation, and neuronal signalling. GPCR’s have been shown to be important drug targets because 30- 50 percent of all pharmaceutical compounds target GPCRs and GPCR-mediated signaling pathways. In this study, we predict and validate the existence of G-protein coupled receptors in the Schistosome genome to provide a resource for future drug discovery efforts.