Chagas disease, caused by Trypanosoma cruzi, the most common cause of congestive heart failure-related mortality and morbidity of humans, is endemic in Latin America. Continuous immigration from endemic areas of South and Central America has increased the risk of exposure of the U.S. population to chagas disease as well. The precise mechanisms leading to ventricular dilation and myocardial hypertrophy, observed in chagasic patients, are not well understood. The present studies are aimed at understanding the role of host gene regulation in the pathogenesis of chagasic cardiomyopathy. Our preliminary studies have suggested that the progression of chagasic myocarditis is associated with aberrations in the expression of cardiac contractile proteins and an imbalance in the mitochondrial energy metabolism proteins. In this project, we propose to investigate the molecular events that might affect the host mitochondrial function and initiate the imbalance of cytoskeletal proteins during the progression of chagas disease. Our hypothesis is that the inflammatory mechanisms elicited to control the pathogen might adversely affect the host mitochondria at the DNA, RNA or protein levels, resulting in a feedback cycle of progressively greater levels of reactive oxidant production and mitochondrial dysfunction. It is possible that reactive oxygen provides a stimuli for initiation of cardiac hypertrophy, and might be the critical determinant in reformatting of myocytes and loss of contractile function observed in chagasic patients. The proposed studies will determine the pathophysiological contribution of host mitochondrial abnormalities in the progression of chagas disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI053098-02
Application #
6661940
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Wali, Tonu M
Project Start
2002-09-30
Project End
2004-09-29
Budget Start
2003-09-30
Budget End
2004-09-29
Support Year
2
Fiscal Year
2003
Total Cost
$74,500
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Ba, Xueqing; Garg, Nisha Jain (2011) Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol 178:946-55
Zacks, Michele A (2007) Impairment of cell division of Trypanosoma cruzi epimastigotes. Mem Inst Oswaldo Cruz 102:111-5
Wen, Jian-jun; Yachelini, Pedro C; Sembaj, Adela et al. (2006) Increased oxidative stress is correlated with mitochondrial dysfunction in chagasic patients. Free Radic Biol Med 41:270-6
Zacks, Michele A; Garg, Nisha (2006) Recent developments in the molecular, biochemical and functional characterization of GPI8 and the GPI-anchoring mechanism [review]. Mol Membr Biol 23:209-25
Wen, Jian-Jun; Bhatia, Vandanajay; Popov, Vsevolod L et al. (2006) Phenyl-alpha-tert-butyl nitrone reverses mitochondrial decay in acute Chagas' disease. Am J Pathol 169:1953-64
Estrada-Franco, Jose G; Bhatia, Vandanajay; Diaz-Albiter, Hector et al. (2006) Human Trypanosoma cruzi infection and seropositivity in dogs, Mexico. Emerg Infect Dis 12:624-30
Zacks, Michele A; Wen, Jian-Jun; Vyatkina, Galina et al. (2005) An overview of chagasic cardiomyopathy: pathogenic importance of oxidative stress. An Acad Bras Cienc 77:695-715
Garg, Nisha (2005) Mitochondrial disorders in chagasic cardiomyopathy. Front Biosci 10:1341-54
Wen, Jian-Jun; Garg, Nisha (2004) Oxidative modification of mitochondrial respiratory complexes in response to the stress of Trypanosoma cruzi infection. Free Radic Biol Med 37:2072-81
Bhatia, Vandanajay; Sinha, Mala; Luxon, Bruce et al. (2004) Utility of the Trypanosoma cruzi sequence database for identification of potential vaccine candidates by in silico and in vitro screening. Infect Immun 72:6245-54

Showing the most recent 10 out of 14 publications