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Comparative and functional genomics of C. neoformans

Award Number: R01AI053721
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: 08/01/2003
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Comparative and functional genomics of C. neoformans - Project Summary/Abstract. Recent estimates indicate that meningoencephalitis caused by the pathogenic fungus Cryptococcus neoformans is responsible 15% of deaths in AIDS patients. Along with other fungal pathogens, C. neoformans is therefore a major threat to the 37 million people worldwide living with HIV. A complex of related species originally designated Cryptococcus gattii has recently emerged as a primary pathogen of immunocompetent people. The long-term goal of our research program is to acquire knowledge that will lead to new strategies to combat cryptococcal infections. In particular, we are working to acquire a detailed understanding of the factors required for fungi to proliferate in vertebrate hosts. In particular, we seek to identify new targets for therapy. Our focus is on iron as an essential nutrient for pathogen proliferation and an important indicator of the host environment. Iron is especially important because mammals actively withhold iron from pathogens through a process called nutritional immunity. Pathogens must therefore be able to successfully compete for iron in order to cause disease. We have shown that iron influences the growth of C. neoformans and also the size of the polysaccharide capsule that is the major virulence factor. Our efforts have focused on characterizing the mechanisms of iron sensing and exploiting the regulatory information to identify targets required for iron acquisition. The first specific aim is to characterize the monothiol glutaredoxin Grx4 as a key sensor of iron availability. Grx4 interacts with the iron regulator Cir1 and the proteins regulate iron homeostasis and the expression of virulence factors. We seek to understand the mechanisms of iron sensing and how the iron signal influences gene expression. A second specific aim will investigate the interaction of Grx4 with a network of transcription factors. Two strong candidates have been identified (HapX and Gat201) and the interactions and regulatory influences of these proteins with Grx4 will be characterized. A final specific aim is based on highly productive genetic screens that identified components of the intracellular machinery for heme trafficking. Mutants lacking trafficking functions for heme acquisition will be constructed and tested in mouse inhalation models of cryptococcosis. Additionally, a heme sensor has been developed to detect heme availability in trafficking mutants in culture and in cryptococcal cells during proliferation in different host tissue locations. Overall, these studies will provide a comprehensive view the integration of iron sensing with the regulation of uptake strategies that are critical during cryptococcosis. !


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: 2024 ( Subtotal = $328,566 )
2024	2024	THE UNIVERSITY OF BRITISH COLUMBIA	224-6328 MEMORIAL RD	VANCOUVER	BC			CAN	Allergy and Infectious Diseases Research	000	20	12/14/2023	NON-COMPETING CONTINUATION	$298,143
2024	2024	THE UNIVERSITY OF BRITISH COLUMBIA	224-6328 MEMORIAL RD	VANCOUVER	BC			CAN	Allergy and Infectious Diseases Research	001	20	4/18/2024	NON-COMPETING CONTINUATION	$30,423
														Subtotal = $328,566

Issue Date FY: 2023 ( Subtotal = $328,566 )
2023	2023	UNIVERSITY OF BRITISH COLUMBIA, THE	6190 AGRONOMY RD STE 102	VANCOUVER	BC			CAN	Allergy and Infectious Diseases Research	000	19	12/5/2022	NON-COMPETING CONTINUATION	$328,566
														Subtotal = $328,566

Issue Date FY: 2022 ( Subtotal = $328,566 )
2022	2022	UNIVERSITY OF BRITISH COLUMBIA, THE	6190 AGRONOMY RD STE 102	VANCOUVER	BC			CAN	Allergy and Infectious Diseases Research	000	18	12/22/2021	NON-COMPETING CONTINUATION	$328,566
														Subtotal = $328,566

Issue Date FY: 2021 ( Subtotal = $328,566 )
2021	2021	UNIVERSITY OF BRITISH COLUMBIA, THE	6190 AGRONOMY RD STE 102	VANCOUVER	BC			CAN	Allergy and Infectious Diseases Research	000	17	12/28/2020	NON-COMPETING CONTINUATION	$328,566
														Subtotal = $328,566

Issue Date FY: 2020 ( Subtotal = $328,566 )
2020	2020	UNIVERSITY OF BRITISH COLUMBIA, THE	6190 AGRONOMY RD STE 102	VANCOUVER	BC	V6T 1Z3		CAN	Allergy and Infectious Diseases Research	001	16	1/9/2020	COMPETING CONTINUATION	$328,566
2020	2018	UNIVERSITY OF BRITISH COLUMBIA, THE	6190 AGRONOMY RD STE 102	VANCOUVER	BC	V6T 1Z3		CAN	Allergy and Infectious Diseases Research	002	15	7/16/2020	NON-COMPETING CONTINUATION	$0
2020	2018	UNIVERSITY OF BRITISH COLUMBIA, THE	6190 AGRONOMY RD STE 102	VANCOUVER	BC	V6T 1Z3		CAN	Allergy and Infectious Diseases Research	000	15	1/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $328,566

Issue Date FY: 2018 ( Subtotal = $290,407 )
2018	2018	UNIVERSITY OF BRITISH COLUMBIA, THE	6190 AGRONOMY RD STE 102	VANCOUVER	BC	V6T 1Z3		CAN	Allergy and Infectious Diseases Research	000	15	2/22/2018	NON-COMPETING CONTINUATION	$290,407
														Subtotal = $290,407

Issue Date FY: 2017 ( Subtotal = $290,407 )
2017	2017	UNIVERSITY OF BRITISH COLUMBIA, THE	6190 AGRONOMY RD STE 102	VANCOUVER	BC	V6T 1Z3		CAN	Allergy and Infectious Diseases Research	000	14	2/16/2017	NON-COMPETING CONTINUATION	$290,407
														Subtotal = $290,407

Issue Date FY: 2016 ( Subtotal = $290,406 )
2016	2016	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	000	13	2/12/2016	NON-COMPETING CONTINUATION	$290,406
														Subtotal = $290,406

Issue Date FY: 2015 ( Subtotal = $283,793 )
2015	2015	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	000	12	2/20/2015	NON-COMPETING CONTINUATION	$283,793
														Subtotal = $283,793

Issue Date FY: 2014 ( Subtotal = $283,793 )
2014	2014	UNIVERSITY OF BRITISH COLUMBIA	**	VANCOUVER, B C		00000		CAN	Allergy and Infectious Diseases Research	002	11	7/22/2014	COMPETING CONTINUATION	$0
2014	2014	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	000	11	3/7/2014	COMPETING CONTINUATION	$283,793
2014	2013	UNIVERSITY OF BRITISH COLUMBIA	**	VANCOUVER, B C		00000		CAN	Allergy and Infectious Diseases Research	001	10	3/7/2014	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $283,793

Issue Date FY: 2013 ( Subtotal = $244,990 )
2013	2013	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	001	10	5/15/2013	EXTENSION WITH OR WITHOUT FUNDS	-$20,220
2013	2013	UNIVERSITY OF BRITISH COLUMBIA	**	VANCOUVER, B C		00000		CAN	Allergy and Infectious Diseases Research	002	10	3/7/2014	EXTENSION WITH OR WITHOUT FUNDS	$0
2013	2013	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	000	10	1/4/2013	EXTENSION WITH OR WITHOUT FUNDS	$265,210
														Subtotal = $244,990

Issue Date FY: 2012 ( Subtotal = $260,628 )
2012	2012	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	000	9	1/31/2012	NON-COMPETING CONTINUATION	$260,628
														Subtotal = $260,628

Issue Date FY: 2011 ( Subtotal = $254,719 )
2011	2011	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	000	8	1/5/2011	NON-COMPETING CONTINUATION	$236,927
2011	2011	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	001	8	8/16/2011	NON-COMPETING CONTINUATION	$17,792
														Subtotal = $254,719

Issue Date FY: 2010 ( Subtotal = $266,586 )
2010	2010	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	000	7	1/12/2010	NON-COMPETING CONTINUATION	$266,586
														Subtotal = $266,586

Issue Date FY: 2009 ( Subtotal = $254,989 )
2009	2009	UNIVERSITY OF BRITISH COLUMBIA	2329 West Mall	VANCOUVER, B C				CAN	Allergy and Infectious Diseases Research	000	6	1/12/2009	COMPETING CONTINUATION	$254,989
														Subtotal = $254,989

Issue Date FY: 2007 ( Subtotal = $230,408 )
2007	2007	UNIVERSITY OF BRITISH COLUMBIA	**	VANCOUVER, B C		00000		CAN	Allergy and Infectious Diseases Research	000	5	3/22/2007	NON-COMPETING CONTINUATION	$230,408
														Subtotal = $230,408

Issue Date FY: 2006 ( Subtotal = $237,290 )
2006	2006	UNIVERSITY OF BRITISH COLUMBIA	**	VANCOUVER, B C		00000		CAN	Allergy and Infectious Diseases Research	000	4	1/26/2006	NON-COMPETING CONTINUATION	$237,290
														Subtotal = $237,290

Issue Date FY: 2005 ( Subtotal = $243,000 )
2005	2005	UNIVERSITY OF BRITISH COLUMBIA	**	VANCOUVER, B C		00000		CAN	Microbiology and Infectious Diseases Research	000	3	1/18/2005	NON-COMPETING CONTINUATION	$243,000
														Subtotal = $243,000

Issue Date FY: 2004 ( Subtotal = $243,000 )
2004	2004	UNIVERSITY OF BRITISH COLUMBIA	**	VANCOUVER, B C		00000		CAN	Microbiology and Infectious Diseases Research	000	2	2/3/2004	NON-COMPETING CONTINUATION	$243,000
														Subtotal = $243,000

Issue Date FY: 2003 ( Subtotal = $121,500 )
2003	2003	UNIVERSITY OF BRITISH COLUMBIA	**	VANCOUVER, B C		00000		CAN	Microbiology and Infectious Diseases Research	000	1	7/17/2003	NEW	$121,500
														Subtotal = $121,500

Grand Total All Awards = $5,438,746

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Comparative and functional genomics of C. neoformans

Award Number: R01AI053721

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: 08/01/2003

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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