Minority Predoctoral Fellowship Program

Meharry Medical College, Nashville TN

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Trypanosoma cruzi, the causative agent of Chagas' disease, is a blood and tissue parasite whose invasive trypomastigote stage must attach to and enter mammalian cells to complete its intracellular development and disseminate infection. To accomplish this goal, it must first crossthe meshwork of the extracellular matrix (ECM) inwhich host cells are interacting. Trypomastigotes possess receptors for host ECM proteins on their surfaces. Recent evidence has shown that the parasite uses released trans-sialidase and mucin molecules to aid in its attachment and entry into cells. The long-term goal is to understand the molecular mechanisms that allow T. cruzi to infect mammalian cells, so that specific molecular intervention strategies can be developed against T. cruzi infection. This application's objective is to understand how T. cruzi uses the extracellular matrix in order to establish infectionin mammalian cells. My preliminary studies using high density cDNA microarray technology and real-time PCR indicatesthat T. cruzi trypomastigotes release surface molecules to up-regulate gone transcription of laminin and thrombospondin in human coronary artery smooth muscle cells. Furthermore, incubation of these cells with trypanosome released molecules increases infection significantly. Based on these findings, the hypothesis of this application is that released surface molecules of invasive forms of T. cruzi target host cells to up-regulate the expression of laminin and thrombospondin in order to recruittrypomastigotes to enhance infection. In order to test this hypothesis the following specific aims are proposed (i) to determine the extent to which RNA interference (RNAi) of laminin I and thrombospondin I reduces T. cruzi infection of hostcells, and (ii) to determine the ability of antibodies to laminin I and thrombospondin I to reduce T. cruzi infection in cells exposed to trypomastigote released molecules.