Patients with Chagas' disease, caused by Trypanosoma cruzi infection, exhibit neural degeneration in the acute phase, neuroregeneration in the chronic indeterminate (asymptomatic) phase, and degeneration of neurons in the chronic symptomatic phase. Most patients remain asymptomatic and with signs of neuronal regeneration for years or decades. Some asymptomatic patients progress to the chronic, fatal chronic disease stage. It remains unknown why patients can remain asymptomatic and with signs of neural regeneration for decades while others develop neurodegeneration later in life. Recent studies demonstrate that T. cruzi expresses surface membrane-bound and shed parasite-derived mimic of neurotrophic factors (PDNF), formerly known as neuraminidase/trans-sialidase, that potently promotes survival of several types of neurons, Schwann cells, and astrocytes. A major and wide audience-reaching finding in the previous five years was that PDNF induces survival and differentiation of neurons by binding and activating TrkA nerve growth factor (NGF) receptor tyrosine kinase. This unique result opens up many interesting avenues to understand the molecular basis of a microbial invader of the nervous system, specifically whether T. cruzi, via PDNF, like authentic host growth factors, recognizes other neurotrophin receptors, triggers off neurotransmitter rate-limiting enzymes through Trks receptors, bear neurotrophin motifs that can be exploited as synthetic peptides to reverse neuronal and glial damage, and elicit autoimmune responses to Trks that might activate or inhibit receptor function. The project will utilize a combination of cell biology, biochemistry, genetics, and immunochemical approaches to identify and characterize the interaction of TrkA and other receptors with PDNF and the novel Trk autoantibodies. Most likely, the outcome of the proposed studies will provide insights into the pathogenesis of Chagas' disease, particularly neuroregeneration, and lead to the development of compounds, principally NGF-like peptidomimetics, to treat not only Chagas' disease but also other neurodegenerative disorders such as Parkinson's disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS040574-06
Application #
6969457
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Nunn, Michael
Project Start
2000-07-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
6
Fiscal Year
2005
Total Cost
$378,094
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Aridgides, Daniel; Salvador, Ryan; PereiraPerrin, Mercio (2013) Trypanosoma cruzi coaxes cardiac fibroblasts into preventing cardiomyocyte death by activating nerve growth factor receptor TrkA. PLoS One 8:e57450
Aridgides, Daniel; Salvador, Ryan; PereiraPerrin, Mercio (2013) Trypanosoma cruzi highjacks TrkC to enter cardiomyocytes and cardiac fibroblasts while exploiting TrkA for cardioprotection against oxidative stress. Cell Microbiol 15:1357-66
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Weinkauf, Craig; Pereiraperrin, Mercio (2009) Trypanosoma cruzi promotes neuronal and glial cell survival through the neurotrophic receptor TrkC. Infect Immun 77:1368-75
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Lu, Bo; PereiraPerrin, Mercio (2008) A novel immunoprecipitation strategy identifies a unique functional mimic of the glial cell line-derived neurotrophic factor family ligands in the pathogen Trypanosoma cruzi. Infect Immun 76:3530-8

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