Project Summary
The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical
disease which causes severe morbidity, mortality, and economic burden in afflicted individuals. The disease,
originally endemic in Latin American countries, has now become a new global health problem in all major
economically advanced countries due to modern globalization. About 30% of T. cruzi infected individuals
eventually present with cardiac, gastrointestinal tract and/or neurological disorders or a combination thereof.
Megacolon, one of Chagas disease major pathologies, is accompanied by an enlarged, fibrotic gastrointestinal
tract and GI motility disorders. The mechanisms through which T. cruzi infection causes cardiac, gastrointestinal
and neurological disorders in afflicted individuals remains under investigation. The objective of this proposal
is to decipher the molecular mechanisms dysregulated by T. cruzi during early infection that contribute
to megacolon pathology. The hippo signaling pathway has been identified as a contributor to fibrotic disease
across tissue types. Activation of downstream hippo effector molecule YAP initiates transcription of fibrotic
genes. We recently showed that T. cruzi activates YAP nuclear translation during the early phase of infection of
heart endothelial cells. Thombospondin-1 (TSP-1) was previously shown to be upregulated by the parasite in
order to facilitate infection. Knockout of TSP-1 in heart endothelial cells decreased YAP mean fluorescence
intensity within the nucleus, indicating that TSP-1 actively interacts with the hippo signaling pathway during T.
cruzi infection. PIWI-interacting RNAs (piRNAs), a class of small noncoding RNAs, contribute to gastrointestinal
diseases such as gastric cancer, colon cancer, and colorectal cancer. We recently showed that piRNAs can
target and regulate genes involved in T. cruzi pathogenesis, such as TGFB1, FOS, and NFATC2. However, the
role of piRNAs have not been investigated in colon cells during T. cruzi infection. Based on these observations,
we hypothesize that the parasite dysregulates the hippo signaling pathway and piRNAs during the early phase
of infection. The hypothesis will be evaluated with the following specific aims: (1) Evaluate the dysregulation of
hippo signaling pathway during early phase of T. cruzi infection and (2) Asses the role of piRNAs and PIWIL
proteins in the regulation of downstream profibrotic genes during the early phase of infection. This project is
significant because it will: identify the role of hippo signaling during T. cruzi infection of colon cells; delineate
TSP-1 and hippo signaling interplay during parasite infection; characterize the functional roles of PIWIL proteins
and piRNAs shown to be increased during infection using primary human colon epithelial and smooth muscle
cells. During the fellowship training period, I will be able to solidify and gain new technical skills, prepare
manuscripts, and participate in career developing activities such as scientific communication, scientific writing,
and teaching. Meharry Medical College and Meharry-Vanderbilt alliance provide access to equipment for this
project.