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Principal Investigator: James J Collins
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $460,972
Funding agency: National Institute of Allergy and Infectious Diseases
Schistosomiasis ranks second (behind malaria) as the world’s most devastating parasitic disease.
Despite this, treatment relies on a single drug, Praziquantel (PZQ), that has marginal efficacy.
This disease is caused by Schistosoma flatworms (schistosomes) that live in the vasculature,
producing eggs that spur a variety of chronic pathologies that are exacerbated by the fact that
schistosomes can survive in the blood for decades. How these parasites thrive in this hostile
environment remains an open question. Our group discovered that adult schistosomes possess
a population of somatic stem cells, neoblasts, that are critical for tissue renewal. During our
studies of these cells we made a surprising discovery: mechanical injury induces a massive
increase in neoblast proliferation at the site of wounding. Because this mirrors what happens in
highly regenerative free-living planarian flatworms, we reasoned that schistosomes may possess
an uncharacterized regenerative capacity. Whole-body regeneration (i.e., regenerating
amputated heads) is not known to occur in schistosomes; yet, classic studies suggest that
treatment of adult worms with sub-lethal doses of PZQ results in extensive tissue damage that
the worms can repair. Likewise, we find that sublethal concentrations of PZQ induce neoblast
proliferation in adult parasites. Furthermore, rapidly growing juvenile schistosomes, which have a
massive number of neoblasts, are refractory to PZQ. Thus, PZQ sensitivity and neoblast number
are inversely correlated. Given these data, we hypothesize that neoblasts fuel regenerative
responses in the worm and we predict these regenerative responses are critical to the parasite’s
ability to respond to insults in vivo, including PZQ treatment. To test this hypothesis, we propose
two specific aims. In Specific Aim 1, we will use single cell RNA sequencing to describe the
cellular lineages that operate during parasite development and determine whether these linages
programs are “reactivated” in adult worms following injury. In Specific Aim 2, we will evaluate
how well schistosomes are able to restore form and function to their tissues following injury and
the extent to which tissue repair relies on neoblasts. We will additionally determine whether
neoblast-driven regenerative responses are essential for juvenile and adult parasite survival
following PZQ administration in vivo. Together, these studies will be the first to explore
schistosome regenerative responses on a molecular level. Because we predict that neoblasts
mediate tissue repair following PZQ-induced damage, these studies could also suggest that
targeting neoblasts may enhance the efficacy of PZQ, thereby transforming how we treat this
disease.
Terms: <21+ years old><Address><Adolescent><Adolescent Youth><Adult><Adult Human><Atlases><Behavior><Bilharzia><Bilharziasis><Biology><Blood><Blood Reticuloendothelial System><Body Tissues><Cell Body><Cells><Chronic><Communities><Data><Development><Disease><Disorder><Dose><Drugs><Environment><Failure><Flatworms><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Gene Expression><Generalized Growth><Genes><Growth><Human><Injury><Malaria><Mechanics><Mediating><Medication><Modeling><Modern Man><Modernization><Molecular><Molecular Analysis><Muscle><Muscle Tissue><Natural regeneration><Outcome><Output><Paludism><Parasites><Parasitic Diseases><Pathology><Pharmaceutical Preparations><Planarians><Plasmodium Infections><Platyhelminthes><Platyhelminths><Play><Population><Prasiquantel><Praziquantel><Process><Progenitor Cells><Proliferating><Public Health><Refractory><Regeneration><Regenerative capacity><Regenerative response><Research><Research Resources><Resources><Role><S mansoni><S. mansoni><Schistosoma><Schistosoma mansoni><Schistosome><Schistosomiasis><Site><Skin><Specific qualifier value><Specified><Testing><Tissue Growth><Tissues><adult progenitor><adult stem cell><adulthood><combat><developmental><drug/agent><egg><fascinate><flow cytophotometry><human pathogen><in vivo><injuries><injury response><juvenile><juvenile human><mechanic><mechanical><muscular><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ontogeny><pathogen><progenitor biology><progenitor cell biology><programs><regenerate><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regeneration ability><regeneration capacity><regeneration response><regenerative><repair><repaired><response to injury><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><somatic progenitor><somatic stem cell><stem and progenitor biology><stem cell biology><stem cells><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><tissue wound><tool><wound><wounding><wounds>