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ANALYSIS OF TRYPANOSOME MRNA SYNTHESIS BY GENE TRANSFER

Award Number: R01AI029478
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/26/2009
PERIOD OF PERFORMANCE END DATE: 08/31/2011

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ANALYSIS OF TRYPANOSOME MRNA SYNTHESIS BY GENE TRANSFER - DESCRIPTION (provided by applicant): Trypanosome-related disease is responsible for significant devastation of productive human lives and high mortality rates throughout the world. The trypanosome transcriptional machinery appears to exhibit intriguing differences from the more conserved machineries of other, better- studied eukaryotes (yeast and mammals). For example, Trypanosoma brucei and other members of the trypanosomatid family contain an unusual RNA polymerase II enzyme and what appears to be an abridged set of transcription factors. Moreover, pre-mRNA start sites remain elusive and transcription initiation is not coordinated with mRNA 5' capping. These mechanistic differences provide a compelling argument for studies into the structure and function of RNA polymerase II- dependent processes in trypanosomes, with the ultimate goals of enhancing our understanding of this evolutionarily diverse process, and developing organism-specific chemotherapies. Although our ultimate objective is to understand the mechanism of RNA polymerase II- dependent gene expression, our short-term goals will focus on characterizing the proteins and sequences that are known, or suspected, to function in pre-mRNA synthesis. To date, we have shown that tSNAPc, tTBP, TFIIB, TFIIA-gamma and RNA polymerase II assemble at the SL RNA gene promoter and are necessary to direct SL RNA synthesis. Because RNA polymerase II is also required for pre-mRNA synthesis, the current proposal will extend analyses of these proteins, as well as several novel RNA polymerase II-interacting proteins recently identified in our lab, to genomic loci thought to direct pre-mRNA expression. The mechanism of pre-mRNA gene expression will be investigated using the following two complementary approaches. First, the function of purified protein factors and DNA sequences will be determined by in vitro transcription studies developed in several laboratories, including our own, in combination with protein-protein and protein-DNA interaction studies. A second approach will exploit in vivo studies, originally developed by others, to assess the function of each protein in cell viability and pre-mRNA expression. These studies are expected to provide us with interesting new insights into the diverse mechanisms by which eukaryotes accomplish fundamentally similar ends, as well as potential targets for drug therapy against what remains a wide-spread and crippling pathogen. PUBLIC HEALTH RELEVANCE: Pathogenic trypanosomes are a major, worldwide public health scourge. In Africa, Trypanosoma brucei ssp. infect humans and domestic cattle, causing African sleeping sickness and Nagana, respectively. Human infection by the subspecies T. b. gambiense and rhodesiense are responsible for almost 2 million disability-adjusted life-years and an estimated 48,000 deaths each year. In the Western hemisphere, trypanosome infection causes fatal enlargement of the colon, as well as serious cardiomyopathy known as Chagas' disease. Approximately 11 million people are afflicted with Chagas' disease and 45,000 people die yearly. In South Asia, South America, and the Middle-East, a closely related group of parasites, the Leishmania, cause debilitating and often fatal Leishmaniasis. Not surprisingly, this disease is a problem for American troops in Iraq and Afghanistan; more than 700 cases have been diagnosed in returning military personnel. At present, there are no vaccines to protect humans from trypanosomal infections and current drugs are toxic, ineffective and expensive. The goal of our biomedical work is to define unique features of trypanosome biology and then to exploit these traits for the design of anti-parasitic chemotherapies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2010 ( Subtotal = $405,360 )
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	000	19	8/10/2010	NON-COMPETING CONTINUATION	$405,360
														Subtotal = $405,360

Issue Date FY: 2009 ( Subtotal = $405,360 )
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	002	18	9/18/2009	COMPETING CONTINUATION	$405,360
2009	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	000	17	6/11/2009	NON-COMPETING CONTINUATION	$0
2009	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	001	17	9/18/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $405,360

Issue Date FY: 2008 ( Subtotal = $463,458 )
2008	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	000	17	2/11/2008	NON-COMPETING CONTINUATION	$463,458
														Subtotal = $463,458

Issue Date FY: 2007 ( Subtotal = $466,883 )
2007	2007	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	000	16	3/26/2007	NON-COMPETING CONTINUATION	$466,883
														Subtotal = $466,883

Issue Date FY: 2006 ( Subtotal = $466,172 )
2006	2006	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	000	15	3/3/2006	NON-COMPETING CONTINUATION	$466,172
														Subtotal = $466,172

Issue Date FY: 2005 ( Subtotal = $443,340 )
2005	2005	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	000	14	1/31/2005	NON-COMPETING CONTINUATION	$443,340
														Subtotal = $443,340

Issue Date FY: 2004 ( Subtotal = $430,427 )
2004	2004	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	000	13	2/13/2004	COMPETING CONTINUATION	$430,427
														Subtotal = $430,427

Issue Date FY: 2003 ( Subtotal = $386,409 )
2003	2003	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	30 BERGEN ST, ADM BLDG #11	NEWARK	NJ	07107	ESSEX	USA	Microbiology and Infectious Diseases Research	000	12		NON-COMPETING CONTINUATION	$386,409
														Subtotal = $386,409

Issue Date FY: 2002 ( Subtotal = $415,054 )
2002	2002	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	30 BERGEN ST, ADM BLDG #11	NEWARK	NJ	07107	ESSEX	USA	Microbiology and Infectious Diseases Research	001	11	2/11/2002	SUPPLEMENT FOR EXPANSION	$39,900
2002	2002	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	30 BERGEN ST, ADM BLDG #11	NEWARK	NJ	07107	ESSEX	USA	Microbiology and Infectious Diseases Research	000	11	12/17/2001	NON-COMPETING CONTINUATION	$375,154
														Subtotal = $415,054

Issue Date FY: 2001 ( Subtotal = $364,227 )
2001	2001	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	30 BERGEN ST, ADM BLDG #11	NEWARK	NJ	07107	ESSEX	USA	Microbiology and Infectious Diseases Research	000	10	1/1/2001	NON-COMPETING CONTINUATION	$364,227
														Subtotal = $364,227

Issue Date FY: 2000 ( Subtotal = $353,617 )
2000	2000	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	000	9	1/31/2000	NON-COMPETING CONTINUATION	$353,617
														Subtotal = $353,617

Issue Date FY: 1999 ( Subtotal = $284,977 )
1999	1999	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Microbiology and Infectious Diseases Research	000	8	7/29/1999	COMPETING CONTINUATION	$284,977
														Subtotal = $284,977

Grand Total All Awards = $4,885,284

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ANALYSIS OF TRYPANOSOME MRNA SYNTHESIS BY GENE TRANSFER

Award Number: R01AI029478

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/26/2009

PERIOD OF PERFORMANCE END DATE: 08/31/2011

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