Wednesday, April 2, 2025
4/2/2025
Functional interrogation of parasitic flatworm TRPM channels to identify novel anthelmintics - PROJECT SUMMARY Praziquantel (PZQ), a drug used clinically for four decades, is essential for treatment of many neglected tropical parasitic diseases; PZQ is the key therapy for treating schistosomiasis, a disease that afflicts over 200 million people worldwide and it is classified as an essential medication by the World Health Organization. However, heavy reliance on PZQ has several limitations. One challenge has been the lack of understanding of how PZQ works, as no molecular target in parasites has been identified. Additionally, sensitivity of parasitic flatworms to PZQ varies, leading to different clinical dosages being required for treating different infections. Infections caused by pseudophyllidean cestodes, the causative agents of long lasting, sometimes fatal diseases such as sparganosis (Spirometra spp. and Sparganum spp.) and diphyllobothriasis (Diphyllobothrium spp.) currently lack an effective drug treatment. My sponsor's laboratory (Dr. Marchant) recently identified a target for PZQ in parasitic flatworms: a Ca2+ permeable ion channel in the transient receptor potential melastatin family (TRPMPZQ). Resolution of this target provided an explanation for the different sensitivity of parasites to PZQ, as the binding pockets of TRPMPZQ in tapeworms with low sensitivity to PZQ contain two key natural amino acid variants that differ from the schistosome TRPMPZQ pocket. I hypothesize that these differences underlie the decreased sensitivity of these tapeworms to PZQ. In Aim 1, I will functionally profile cestode TRPMPZQ channels with the goal of discovering novel chemotypes that activate TRPMPZQ in parasite species that show poor sensitivity to PZQ. This Aim will provide me training in cell culture, molecular cloning, fluorescence reporter methods and experience developing a robust, reproducible drug screening pipeline. This effort will also be the first study of a tapeworm ion channel by high-throughput drug screening. Next, building on my progress evidencing the druggability of this family of ion channels, I propose in Aim 2 to identify and functionally profile other TRPM paralogs in schistosomes in vitro and by functional genetic manipulation in the parasites themselves. The work will utilize a broad range of experimental methods important for my training, including bioinformatic analysis, generation of stable cell lines, and methods to localize and manipulate gene products within parasites. This work will likely generate new tools useful for the broader molecular parasitological community. Overall my training plan will help me master skillsets to work with parasitic flatworms and manipulate their gene products in vitro (Aim 1) and ex vivo (Aim 2). My training and mentoring plan would provide opportunities for participation at conferences and enrollment in courses on parasitology, drug design, and global health, equipping me with skills to work towards a career focused on efforts to eradication neglected tropical diseases.
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