Parasitic flatworms, such as tapeworms, have global reach and cause a wide variety of symptoms from intestinal distress and lethargy to organ failure, seizures, and even death. These parasites have complex life cycles and a remarkable capacity for growth, reproduction, regeneration, and longevity. These physiological traits are enabled by stem cells, thus understanding stem cell behaviors and regulation in these parasites has the capacity to uncover a broad range of potential targets that can be exploited for future drug development. My foundational work establishing the rat tapeworm, Hymenolepis diminuta, as a tractable modern model organism and my initial characterization of stem cells and regeneration in this system make it ideal for this study. My goal is to elucidate stem cell-driven regeneration and reproduction in this tapeworm. I seek to discover the signals that regulate stem cell potency and enable regeneration of tapeworm proglottids, which are each a functional reproductive unit. To this end, I will identify subpopulations of stem cells and functionally assay for pluripotent potential using innovative cell isolation and transplantation methodologies. I have previously shown that microenvironmental signals that regulate regenerative ability are anteriorly biased. Thus, I will undertake high- throughput gene expression screening and RNA interference by targeting factors that are polarized along the anterior-posterior axis across the regeneration-competent tapeworm neck. Furthermore, I will functionally identify genetic regulators of the germline lineage and investigate the potential plasticity of germ cells, as well as their coordination with mechanisms that govern proglottid regeneration. These innovative studies exploit the natural progression of parasite development to make genetic discoveries and take a stem cell-centric approach to illuminate parasite biology. This is significant as I will be able to make fundamental discoveries in both stem and germ cell biology, as well as in a greater disease-relevant context.
These studies take a stem cell-based view of tapeworm growth, regeneration, and reproduction with the potential to make discoveries about crucial aspects of tapeworm biology as well as broader discoveries in stem and germ cell biology. Completion of the proposed research could aid in the discovery of new drugs to combat diseases caused by these important parasites, which infect both humans and livestock. 1