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Pilot Projects

Project 1: Targeting unique kinetoplastid motility mechanisms to treat pathogenic disease

TI: Joshua Alper, PhD

Flagellar motility is critical to the life cycle and virulence of kinetoplastid pathogens, including trypanosome and leishmania. Kinetoplastid flagella beat with a bending wave that propagates from its tip to its base. This is unlike nearly all other eukaryotes, which beat from the base to the tip, despite nearly identical structures. There are multiple lines of evidence that suggest the coordination and regulation mechanisms of axonemal dyneins, the molecular motors that drive flagellar motility, dictate this unique propagation direction. Our research is to understand the unique features of kinetoplastid flagellar motility using Trypanosoma brucei as a model for highly-conserved kinetoplastid flagella. We will take interdisciplinary approaches, including molecular biology (RNAi cloning, mutagenesis), biochemistry (ion exchange and affinity column chromatography), biophysics (ultrafast dual-trap optical tweezers, total internal reflectance fluorescence microscopy), and bioinformatics. We will integrate the collected quantitative data into multi-scale predictive biophysical models of flagellar waveform propagation direction that will lead to both a fundamental understanding of flagellar waveform propagation direction and ultimately novel treatments for African sleeping sickness, Chagas disease, and leishmaniasis.

Project 2: Biology of Toxoplasma infection

TI: Zhicheng Dou, PhD

Toxoplasma gondii widely infects human population. Approximately, one-third of the human population is infected with Toxoplasma parasites. As an obligate intracellular parasite, Toxoplasma has to invade host cells, replicate, and egress to infect another host cell. My lab focuses on two questions of Toxoplasmainfection. 1) How Toxoplasma uses its proteases to disseminate infection? During the lytic cycle of infection, the parasites secrete proteases to maturate their invasion and egress effectors for their proper functions. One of my publications documented that Toxoplasma regulates the activity of one surface-anchored subtilisin-like protease (TgSUB1) by secreting a polypeptide (Saouros, Dou, Marchant, Carruthers, & Matthews, 2012)Toxoplasma also stores its proteases within the Vacuolar Compartment (VAC), a lysosome-equivalent structure, to catabolize ingested proteins for supporting its intracellular replication (Dou, McGovern, Di Cristina, & Carruthers, 2014). The VAC also can help parasite eat “itself” via an autophagy process to maintain its chronic infection (Di Cristina et al., 2017). 2) How Toxoplasma acquires and utilizes nutrients from host cells? During its intracellular infection stage, Toxoplasma is encapsulated in a membrane-bound niche, termed the parasitophorous vacuole (PV). The membrane of the PV (PVM) limits diffusion of host substances. Moreover, the PV is non-fusogenic, blocking the parasite’s access to ample nutrients generated by the host lysosome. To help acquire host nutrients, Toxoplasma secretes proteins from the unique organelle, the dense granule, that decorate the PV. The putative nutrient pores are believed to be distributed on the PVM, which allow small substances whose molecular weights are less than 1,200 Da to cross. Toxoplasmaalso can utilize a unique structure within the PV, termed intravacuolar membrane network (IVN), to acquire host macromolecular substances via endocytosis (Dou et al., 2014). Using a combination of molecular biology, biochemistry, and cell biological approaches, my laboratory will study these two questions at molecular and cellular levels. Our work will shed light on the development of novel strategies to specifically block the proteolytic activity and the nutrient acquisition within the parasites to benefit clinical management of infection.
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