The human and animal trypanosomiases have major medical, veterinary, and economic consequences. Leishmaniasis and trypanosomiasis cause chronic and sometimes fatal diseases in people in both developing countries and, as travel to these areas increases, in the developed world as well. In areas of South America where T. cruzi is endemic, heart disease (Chagas)is a signification cause of death and disability. Unfortunately, currently available treatments for all trypanosome infections are expensive, potentially toxic and must be administered for long periods of time. New therapeutic approaches are needed and will require a deeper understanding of the molecular biology of the tgrypanosomatidae.
The aim of the investigator is to develop an increased knowledge of parasite growth in order to pinpoint vulnerable aspects of trypanosome biology, which may prove amenable to newer, more efficacious, and less expensive therapies.
The specific aim of this grant is to further our understanding of the regulatory signals involved in mRNA synthesis in trypanosomes. Virtually nothing is known about the proteins that recruit RNA polymerases to DNA to initiation transcription in these medically important protists. A characteristic genetic trait of all trypanosomes is the ability of every trypanosomal mRNA to acquire a spliced leader (SL) sequence prior to transport from the nucleus. The ubiquitous nature of the spliced leader indicates that this short RNA may be essential in mRNA metabolism. We plan to use established biochemical techniques to explore the structure of proteins that interact with the SL RNA gene promoter and direct SL RNA synthesis. These analyses, which will include gene cloning and protein function studies, will help identify the specific mechanisms that trypanosomes employ to accomplish this fundamental cellular process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029478-10
Application #
6341608
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
1991-01-01
Project End
2003-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
10
Fiscal Year
2001
Total Cost
$364,227
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
Liu, Wenzhe; Das, Anish; Morales, Rachel et al. (2012) Chromatin immunoprecipitation and microarray analysis reveal that TFIIB occupies the SL RNA gene promoter region in Trypanosoma brucei chromosomes. Mol Biochem Parasitol 186:139-42
Ibrahim, B Syed; Kanneganti, Nalini; Rieckhof, Gabrielle E et al. (2009) Structure of the C-terminal domain of transcription factor IIB from Trypanosoma brucei. Proc Natl Acad Sci U S A 106:13242-7
Das, Anish; Bellofatto, Vivian (2009) The non-canonical CTD of RNAP-II is essential for productive RNA synthesis in Trypanosoma brucei. PLoS One 4:e6959
Bellofatto, Vivian; Palenchar, Jennifer B (2008) RNA interference as a genetic tool in trypanosomes. Methods Mol Biol 442:83-94
Das, Anish; Banday, Mahrukh; Bellofatto, Vivian (2008) RNA polymerase transcription machinery in trypanosomes. Eukaryot Cell 7:429-34
Bellofatto, Vivian (2007) Pyrimidine transport activities in trypanosomes. Trends Parasitol 23:187-9;discussion 190
Palenchar, Jennifer B; Liu, Wenzhe; Palenchar, Peter M et al. (2006) A divergent transcription factor TFIIB in trypanosomes is required for RNA polymerase II-dependent spliced leader RNA transcription and cell viability. Eukaryot Cell 5:293-300
Das, Anish; Li, Hong; Liu, Tong et al. (2006) Biochemical characterization of Trypanosoma brucei RNA polymerase II. Mol Biochem Parasitol 150:201-10
Das, Anish; Zhang, Qing; Palenchar, Jennifer B et al. (2005) Trypanosomal TBP functions with the multisubunit transcription factor tSNAP to direct spliced-leader RNA gene expression. Mol Cell Biol 25:7314-22
Gilinger, Gwen; Luo, Hua; Bellofatto, Vivian (2004) In vivo transcription analysis utilizing chromatin immunoprecipation reveals a role for trypanosome transcription factor PBP-1 in RNA polymerase III-dependent transcription. Mol Biochem Parasitol 134:169-73

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