This research will be done primarily in San Martin, Argentina, at Fundacion Instituto de Investigaciones Biotecnologicas, Universidad Nacional de General San Martin, in collaboration with Dr. Juan J. Cazzulo, as an extension of NIH Grant 1R01 AI068647. Chemotherapy of Chagas disease is restricted to drugs with relatively high toxicity and limited efficacy. Our research focuses on the rational search for effective chemotherapeutic treatments for T. cruzi by investigating metabolic systems necessary for parasites but without equivalent counterparts in the human host. The response of the parasite to nutritional and hyperosmotic stresses is fundamental for its survival within the vector and mammalian hosts and its study could lead to the finding of novel targets. Stress conditions usually lead to a variety of physiological responses at the cellular level. Stress conditions usually lead to a variety of physiological responses at the cellular level. When epimastigotes of T. cruzi were submitted to hyperosmotic stress the cells reduced their volume without recovery, and up-regulated or down- regulated the expression of a number of genes. Candidate structural RNA motifs were found in the 3'-UTR of several transcripts and enriched in the experimental dataset when comparing over the complete transcriptome. These cis-elements could be involved in post-transcriptional mechanisms underlying a global expression pattern in response to hyperosmotic stress. This proposal will be focused in the following specific aims:
Specific aim 1 : to study the changes in gene expression in T. cruzi submitted to hyperosmotic stress;
Specific aim 2 : to investigate the role of the cis-elements identified in the 3'-UTR of genes affected by hyperosmotic stress in gene expression of T. cruzi.
In the Americas, from Mexico in the North to Argentina and Chile in the South, there are 16 to 19 million people infected with Trypanosoma cruzi, the causative agent of Chagas disease. Estimated yearly incidence amounts to 561,000 cases. Chagas disease is a vector-borne disease that can also be transmitted by blood transfusion and is the leading cause of congestive heart failure in Latin America. Our goal is to find ways of interfering with Trypanosoma cruzi metabolic pathways as a strategy of controlling infections caused by this and similar parasites. The response of T. cruzi to nutritional and hyperosmotic stresses is different from the response of mammalian cells to similar stresses and their study may lead to the discovery of new targets for trypanocidal agents. This work is designed to investigate the roles and significance of these pathways in T. cruzi.
|Li, Zhu-Hong; De Gaudenzi, Javier G; Alvarez, Vanina E et al. (2012) A 43-nucleotide U-rich element in 3'-untranslated region of large number of Trypanosoma cruzi transcripts is important for mRNA abundance in intracellular amastigotes. J Biol Chem 287:19058-69|
|Li, Zhu-Hong; Alvarez, Vanina E; De Gaudenzi, Javier G et al. (2011) Hyperosmotic stress induces aquaporin-dependent cell shrinkage, polyphosphate synthesis, amino acid accumulation, and global gene expression changes in Trypanosoma cruzi. J Biol Chem 286:43959-71|